Doxapram as an additive to propofol sedation for endoscopic retrograde cholangiopancreatography: a placebo-controlled, randomized, double-blinded study.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) requires moderate to deep sedation, usually with propofol. Adverse effects of propofol sedation are relatively common, such as respiratory and cardiovascular depression. This study was conducted to determine if doxapram, a respiratory stimulant, could be used to reduce the incidence of respiratory depression. METHODS: This is a single-center, prospective randomized double-blind study performed in the endoscopy unit of Helsinki University Central Hospital. 56 patients were randomized in a 1:1 ratio to either receive doxapram as an initial 1 mg/kg bolus and an infusion of 1 mg/kg/h (group DOX) or placebo (group P) during propofol sedation for ERCP. Main outcome measures were apneic episodes and hypoxemia (SpO2 < 90%). Mann-Whitney test for continuous variables and Fisher's exact test for discrete variables were used and mixed effects modeling to take into account repeated measurements on the same subject and comparing both changes within a group as a function of time and between the groups. RESULTS: There were no statistically significant differences in apneic episodes (p = 0.18) or hypoxemia (p = 0.53) between the groups. There was a statistically significant rise in etCO2 levels in both groups, but the rise was smaller in group P. There was a statistically significant rise in Bispectral Index (p = 0.002) but not modified Observer's Assessment of Agitation/Sedation (p = 0.21) in group P. There were no statistically significant differences in any other measured parameters. CONCLUSIONS: Doxapram was not effective in reducing respiratory depression caused by deep propofol sedation during ERCP. Further studies are warranted using different sedation protocols and dosing regimens. Clinical trial registration ClinicalTrials.gov ID NCT02171910.

Patient-controlled sedation for ERCP: a randomized double-blind comparison of alfentanil and remifentanil.

BACKGROUND AND STUDY AIMS: Self-administration of a propofol and opioid mixture by patients (patient-controlled sedation, PCS) could offer a practical alternative for individual sedation during endoscopic retrograde cholangiopancreatography (ERCP). However, what would be the most suitable sedative mixture for PCS is unknown. The aim of this study was to compare remifentanil and alfentanil in the PCS during ERCP. PATIENTS AND METHODS: Eighty-one patients undergoing elective ERCP received PCS with propofol and opioid in three different regimens. The concentrations of opioids in the sedative mixture were 0.02 mg/mL in the remifentanil group (R) and 0.04 mg/mL and 0.08 mg/mL in the alfentanil 1 (A1) and alfentanil 2 (A2) groups, respectively. The infusion pump was adjusted to deliver a 1 mL single dose with zero lockout time. We considered PCS as successful if no procedure interruption due to sedation-related complications occurred or if additional propofol was not needed. The consumption of propofol was registered, and sedation levels and vital signs were monitored. Endoscopist and patient satisfaction with sedation were assessed using structured questionnaires. RESULTS: The consumption (SD) of propofol was 177 (105)mg in group R, 197 (88) mg in group A1 and 162 (70)mg in group A2. PCS was successful in 74 /81 (91 %) of sedations, without differences between the groups in terms of propofol consumption, sedation success rate, sedation levels, vital signs, postprocedural pain, and endoscopist and patient satisfaction. Respiratory depression and nausea were observed more frequently with remifentanil than with alfentanil (P < 0.05). CONCLUSIONS: PCS is an acceptable method of sedation for ERCP. The combination of propofol and alfentanil should be recommended because a remifentanil - propofol mixture depresses spontaneous respiration more and produces nausea more frequently.

Effect And Predictive Value Of Routine Preoperative Laboratory Testing For Endoscopic Retrograde Cholangiopancreatography.

BACKGROUND AND AIMS: Several studies and guidelines are questioning routine preoperative laboratory tests in surgical and endoscopic procedures. Their effect in endoscopic retrograde cholangiopancreatography is not currently known. This study was carried out to evaluate the risk of adverse effects in endoscopic retrograde cholangiopancreatography and their association with preoperative lab tests. MATERIALS AND METHODS: A single-center, prospective observational study on all 956 patients undergoing 1196 endoscopic retrograde cholangiopancreatographies in the Endoscopy Unit of Helsinki University Central Hospital from 1 March 2012 to 28 February 2013. Routine preoperative laboratory test results (basic blood count, creatinine, potassium, sodium, international normalized ratio/thromboplastin time, and amylase), health status, medication, and demographic information of all patients were analyzed in relation to adverse effects related to endoscopic retrograde cholangiopancreatography and procedural sedation. RESULTS: Multivariate analysis showed post-endoscopic retrograde cholangiopancreatography pancreatitis (43 cases, 3.6%) to have no association with abnormal routine preoperative laboratory tests. Respiratory depression caused by sedation (128 cases, 11%) was not associated with abnormal routine preoperative laboratory tests, and anemia was found to be a slightly protecting factor. Cardiovascular depression caused by sedation was associated with thrombocytopenia (odds ratio = 1.87, p = 0.025) and, in male patients, hyponatremia (odds ratio = 3.66, p < 0.001). Incidence of other adverse effects was too low for statistical analysis. CONCLUSION: Routine universal preoperative lab testing was not found to be successful in predicting adverse effects in endoscopic retrograde cholangiopancreatography procedures. Laboratory testing should be done focusing on each patient's individual needs.

Mortality in diabetic patients undergoing non-cardiac surgery: a 7-year follow-up study.

BACKGROUND: The prognosis of diabetic patients after non-cardiac surgery remains controversial. This study was designed to compare the long-term mortality between diabetic and non-diabetic control patients undergoing non-cardiac surgery and to evaluate the possible risk factors. METHODS: We investigated 274 consecutive diabetic patients and 282 non-diabetic control patients who underwent non-cardiac surgery within 1 year in a tertiary care hospital in Finland. The control group was matched for the same type of operations. Patients were followed for up to 7 years on average. The main outcome measure was mortality within 7 years. RESULTS: Mortality both in the short-term postoperatively (< or =21 days) and in the long-term (up to 87 (1/2) months) was significantly higher in the diabetic patients compared with the non-diabetic group: 3.5 vs. 0% (P<0.05) and 37.2 vs. 15% (P<0.00001), respectively. The major causes of death among diabetic subjects were diseases of the cardiovascular system (56.8%) compared with non-diabetic patients (18.6%), P<0.0001. We found that diabetes mellitus per se is not a risk factor for post-operative mortality but a combination of variables had a significant effect on both short- and long-term mortality. CONCLUSION: Diabetic patients undergoing non-cardiac surgery had a significantly higher incidence of short-term post-operative and long-term mortality compared with non-diabetic subjects. We propose a model of predictors of death among diabetic individuals undergoing non-cardiac surgery within a 7-year follow-up. The majority of deaths were associated with cardiovascular diseases.

The outcome of pain related undergraduate teaching in Finnish medical faculties.

Little is known about how other than cancer pain related issues are represented in medical education. A standardised questionnaire was mailed to all medical students who graduated from the five Finnish medical schools in 2001. A total of 387 students received the questionnaire and 41% responded. The students had to evaluate the quantity and the quality of pain teaching. The availability and the participation in the advanced courses or research in pain medicine were asked. The students reported how the IASP curriculum on pain had been covered during the studies. Two clinical cases were presented for diagnosis and treatment. In addition to integrated pain teaching, specific pain education was received by 27% of the students. The departments of anaesthesiology were reported as the major deliverers of teaching of pain. The overall ratings of the pain-related teaching of the faculties varied from 3.4 to 4.6 on a scale of 10. Anatomy, biochemistry, physiology and pharmacology of pain were covered well. The definitions of pain, pain research, sociological issues, paediatric, geriatric and mentally retarded patients' pain were taught most poorly. Only 34% of the students had been offered advanced studies and 15% had been offered research projects in pain medicine. The lack of teaching about the concept of a multidisciplinary pain clinic was recognised by almost all students. The clinical problems were excellently solved. In conclusion, the IASP curriculum is well covered in the present programmes in the Finnish medical faculties. However, the quality and the methods of teaching still need improvement.

Pain related undergraduate teaching in medical faculties in Finland.

The present questionnaire study was conducted to examine how teachers in all Finnish medical faculties have included pain teaching in their courses for undergraduate medical students. The study was planned to compare the existing education in Finland with the IASP curriculum on pain for medical schools. In 1991 and 1995 the questionnaire was sent to a total of 135 and 130 university teachers, respectively. The teachers were asked about the quantity and quality of their pain teaching. Teachers' attitudes on pain related teaching were also examined. A Finnish translation of the IASP curriculum was provided, and university teachers were asked to evaluate it and compare it with their current teaching. The educational programs of all universities were also analyzed. After completion of these surveys, representatives of teachers responsible for teaching of pain, and of medical students from all Finnish medical faculties were invited to a meeting to discuss methods for improving and developing education. Completed questionnaires were received from 107 university teachers (78%) in 1991 and from 74 (60%) in 1995. No printed curricula for pain education were found in any university and in all universities pain teaching was provided in an inconsistent way. There were differences, yet statistically non-significant, between the faculties in the pain teaching. No major differences were observed between the two questionnaires. A serious lack of teaching in psychology of pain was a general finding. University teachers were found to have positive attitudes towards developing their teaching of pain. The IASP curriculum has not been fully followed but was considered a valuable tool in planning the educational programs. The curriculum should be distributed directly to the governmental bodies of the universities, since individual university teachers are not necessarily familiar with it. Local associations may have an important role in this distribution as we have shown. This report shows the necessity of changing the attitudes of university teachers providing concrete teaching programs for pain. A multimedia package of pain containing references, video tapes and cd-discs produced by a workshop of IASP would certainly be welcome.

A review of oxycodone's clinical pharmacokinetics and pharmacodynamics.

Oxycodone (14-hydroxy-7,8-dihydrocodeinone) is a strong opioid agonist that is available alone or in combination with mild analgesics. It is suitable for oral administration due to high bioavailability (60%), and may also be given intramuscularly, intravenously, subcutaneously, and rectally; it is not recommended for spinal administration. In analgesic potency, oxycodone is comparable to morphine. With the exception of hallucinations, which may occur more rarely after oxycodone than after morphine, the side effects of these drugs are closely related. The abuse potential of oxycodone is equivalent to that of morphine. The usual indications for oxycodone are severe acute postoperative or posttraumatic pain and cancer pain. When oxycodone is administered, the same precautions should be taken as with morphine or other agonist opioids.

Acute renal injury and dysfunction following elective abdominal aortic surgery.

OBJECTIVES: To evaluate the incidence of kidney injury and acute renal dysfunction (ARD) and associated risk factors in open abdominal aortic surgery. MATERIALS AND METHODS: 69 patients undergoing elective infrarenal aortic repair were included in a prospective study. Anaesthesia and haemodynamic management were standardised targeting a mean arterial pressure (MAP) of 70-90 mmHg, pulmonary artery occlusion pressure of 12-14 mmHg and cardiac index >or=2.4 l/min/m(2). Urinary albumin-creatinine and N-acetyl-B-D-glucosaminidase-creatinine ratios were measured as indicators of kidney injury. The definition of ARD was based on the RIFLE criteria. RESULTS: Kidney injury was found in most patients. ARD developed in 22% of the patients, and acute renal failure in 4%. The patients with ARD were older, and had lower plasma creatinine and estimated GFR before surgery. ARD was associated with intraoperative hypotension (MAP <60 mmHg >15 min), low cardiac index (<2.4 l/min/m(2)), rhabdomyolysis, and early reoperation. Intraoperative hypotension and postoperative low cardiac output were independent risk factors for ARD in multivariate analysis. CONCLUSIONS: Kidney injury occurs in most patients undergoing infrarenal aortic surgery, but only 22% develop acute renal dysfunction. Hypotension and low cardiac output are risk factors that could be avoided by optimizing perioperative management.

Lack of renoprotective effect of i.v. N-acetylcysteine in patients with chronic renal failure undergoing cardiac surgery.

BACKGROUND: Pre-existing chronic renal failure is a significant risk factor for acute renal failure (ARF) after cardiac surgery. N-acetylcysteine (NAC) has been shown to prevent contrast media-induced ARF. Our objective was to evaluate whether i.v. NAC has renoprotective effects in patients with mild renal failure undergoing cardiac surgery. METHODS: In this prospective, randomized, double-blind study, 80 patients with mild to moderate renal failure undergoing elective heart surgery with cardiopulmonary bypass were recruited. All received either i.v. NAC (n=38) or placebo (n=39) at induction of anaesthesia and then up to 20 h. Urine N-acetyl-beta-D-glucosaminidase (NAG) and urine creatinine ratio, plasma creatinine, and serum cystatin C levels indicated renal function. RESULTS: Levels of urinary NAG/creatinine ratio, plasma creatinine and serum cystatin C did not significantly differ between NAC and placebo groups during five postoperative days. Urine NAG/creatinine ratio increased over 30% in 100% of patients in the NAC group vs 92.3% in the placebo group (P=0.081). Plasma creatinine increased by 25% from baseline or over 44 mumol litre(-1) in 42.1% in NAC group vs 48.7% in placebo group (P=0.560). Serum cystatin C exceeded 1.4 mg litre(-1) in 78.9% in NAC group vs 61.5% in placebo group (P=0.096). CONCLUSIONS: Prophylactic treatment with i.v. N-acetylcysteine had no renoprotective effect in patients with pre-existing renal failure undergoing cardiac surgery.

Opioids in anaesthesia: a questionnaire survey in Finland.

A questionnaire was sent to the pharmacies of 88 Finish hospitals with surgical departments to inquire about the consumption of opioids during 1990. Another questionnaire was sent to 480 members of the Finnish Society of Anaesthesiologists to ask how they administer opioids to adult patients. Answers were received from 95% of hospitals and 67% of anaesthetists. Dextropropoxyphene was the most common oral opioid and oxycodone was the most common parenteral opioid used in Finland. Parenteral opioids were consumed almost totally in the hospitals. The anaesthetists reported oxycodone to be the opioid of choice for premedication, postoperative pain and sedation of critically ill patients. Fentanyl was the opioid most commonly used intravenously during balanced anaesthesia and in epidural administration. Epidural opioids were administered by 77% of anaesthetists and patient-controlled analgesia (PCA) technique mostly for intravenous administration by 19%. Only 10% of Finnish anaesthetists were actively involved in the management of chronic pain; the methods they use are discussed. The majority of anaesthetists were satisfied with the currently available opioids.

[Herpes zoster neuralgia--a persistent therapeutic problem]. / Herpes zosterneuralgi--ett envist terapeutiskt problem.

Most patients with acute herpes zoster (AHN) who are younger than 50 yrs recover spontaneously and need no more specific medication than NSAID-analgetics. However, older patients and those treated with immunosuppressive medication are at high risk of developing postherpetic neuralgy (PHN), and may need intensive treatment for severe pain. Unfortunately there is no specific method so far to prevent PHN. In the prevention of PHN some promising results have been gained with antiviral drugs, sympathetic blocks, corticosteroids, psychotropic and anticonvulsive drugs. The earlier any of these treatments is started in AHM, the better results. When PHN has developed, in most cases there is no effective treatment to be offered. In the Pain Clinic of Helsinki University Hospital antidepressive and neuroleptic drugs as well as transcutaneous neurostimulation have been used for PHN treatment.

Liposolubility and protein binding of oxycodone in vitro.

The liposolubility and protein-binding of oxycodone were studied in vitro and compared with other opioids. Liposolubility was assessed by three different methods: 1) the shake-flask method with n-octanol at pH 4-9, 2) measuring the retention time in reversed-phase high-performance liquid chromatography (RP-HPLC) with a LiChrosorb RP-18 and 3) studying the solubility in human epidural and subcutaneous fat. Human fat was obtained from patients undergoing surgery for herniated intervertebral disc. After incubation, pieces of fatty tissue immersed in a buffer solution containing oxycodone, morphine, pethidine or fentanyl for 10-40 min.; tissue pieces were homogenated, opioids extracted and opioid concentrations measured by gas- and high-performance liquid chromatography. The binding of oxycodone, morphine and fentanyl in plasma proteins was studied by ultrafiltration (Amicon-kit). The mean apparent partition coefficients Papp of oxycodone, morphine, pethidine and fentanyl in n-octanol at pH 7 were 0.7, 0.5, 10.5 and 399, respectively. The retention times in RP-HPLC for oxycodone, morphine, pethidine, fentanyl and buprenorphine were 0.6 min., 0.2 min., 2.4 min., 2.3 min. and 10.5 min., respectively. Only buprenorphine and fentanyl appeared to be highly lipophilic in the human fat tissue experiments; no difference was found between epidural or subcutaneous fat in this respect. The in vitro protein binding of oxycodone was 38%, of morphine 31% and of fentanyl 87% in average. It is concluded that, in terms of physiochemical properties, liposolubility and protein-binding, oxycodone resembles morphine more than it does fentanyl.

Antinociceptive effects and central nervous system depression caused by oxycodone and morphine in rats.

Antinociception and central nervous system depression (CNSD) caused by intraperitoneal, intrathecal and subcutaneous administration of oxycodone or morphine were studied in a randomized and blind, saline controlled study in rats. Antinociception was assessed with the tail-flick and hot plate tests. CNSD was assessed by testing the corneal, placing and righting reflexes and with a 4-point catalepsy score. Intraperitoneally and subcutaneously administered oxycodone and morphine were given in doses of 2.5-10 and 5-20 mg kg-1 respectively. The intrathecal doses were 12.5 micrograms and 100 micrograms of oxycodone and 6.25 micrograms and 50 micrograms of morphine. In both nociceptive tests subcutaneously and intraperitoneally administered oxycodone was 2-4 times more potent than morphine, while intrathecal morphine was over 14 times more potent. CNSD was more profound with oxycodone than with morphine after intraperitoneal and subcutaneous administration, but was not observed after intratechal administration of either drug. Differences in opioid receptor affinities, liposolubilities and metabolism are discussed as possible explanations.

The pharmacokinetics of oxycodone after intravenous injection in adults.

Oxycodone chloride (0.07 mg kg-1) was given by intravenous bolus to nine young adult surgical patients on the first postoperative day. Plasma was sampled for up to 12 h. Mean values of t1/2z, CL and Vss were 222 min, 0.78 l min-1 and 2.60 l kg-1, respectively. The concentrations of the metabolite noroxycodone was also measured. The mean AUC(0,12) ratio of noroxycodone to oxycodone was 0.33. Oxymorphone was not detected.

The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects.

1. The pharmacokinetics and metabolism of oxycodone were studied in nine healthy young volunteers in a cross-over study. Each subject received oxycodone chloride once intramuscularly (0.14 mg kg-1) and twice orally (0.28 mg kg-1) at intervals of 2 weeks. A double-blind randomized pretreatment with amitriptyline (10-50 mg a day) or placebo was given prior to oral oxycodone. 2. The concentrations of oxycodone, noroxycodone and oxymorphone in plasma and the 24 h urine recoveries of their conjugated and unconjugated forms were measured by gas chromatography. 3. No differences were found between treatments in mean Cmax and AUC values of oxycodone which varied from 34 to 38 ng ml-1 and from 208 to 245 ng ml-1 h, respectively. The median tmax of oxycodone was 1 h in all groups. The bioavailability of oral relative to i.m. oxycodone was 60%. The mean renal clearance of oxycodone was 0.07-0.08 l min-1. The kinetics of oxycodone were unaffected by amitriptyline. 4. The mean ratio of the AUC(0.24 h) values of unconjugated noroxycodone to oxycodone was 0.45 after i.m. oxycodone and 0.6-0.8 after oral oxycodone. Plasma oxymorphone concentrations were below the limit of the assay. Eight to 14% of the dose of oxycodone was excreted in the urine as unconjugated and conjugated oxycodone over 24 h. Oxymorphone was excreted mainly as a conjugate whereas noroxycodone was recovered mostly in an unconjugated form.

Spinal antinociception by dexmedetomidine, a highly selective alpha 2-adrenergic agonist.

The antinociceptive effects of dexmedetomidine, a highly selective new alpha 2-adrenoceptor agonist, were evaluated in rats after intrathecal, intraperitoneal and subcutaneous administration. Antinociception was tested using the tail-flick method. Both 3 and 6 micrograms of intrathecal dexmedetomidine produced maximal antinociception within 10 min. The effect lasted for up to 6 hr. The smaller dose of 1.5 micrograms produced a mean antinociception of 50% (of the maximum possible effect, MPE%) which lasted for about 2 hr. Subcutaneous atipamezole, a specific alpha 2-adrenergic antagonist completely abolished the antinociception produced by intrathecal dexmedetomidine. When given intraperitoneally, dexmedetomidine produced on average a 50% antinociceptive effect with the highest dose of 60 micrograms/kg. The lower doses of 10 and 30 micrograms/kg were ineffective. After subcutaneous administration a maximal effect was achieved with 120 micrograms/kg, a 70% effect, on average, with 60 micrograms/kg and a short lasting effect of 60% with 30 micrograms/kg. In conclusion, dexmedetomidine is a very potent antinociceptive agent when given intrathecally to rats.

Previous pain experience in women with fibromyalgia and inflammatory arthritis and nonpainful controls.

OBJECTIVE: To examine the frequency of commonly occurring pain and adverse experiences throughout life by self-report in women with fibromyalgia (FM) and chronic inflammatory arthritis (IA) and nonpainful healthy women. METHODS: Fifty-one patients with FM and 44 with IA and 52 nonpainful healthy controls were consecutively interviewed in a tertiary clinic setting regarding the occurrence of lifetime common pain experience and adverse events, as well as a family history of FM and/or a childhood pain environment. RESULTS: Patients with FM reported significantly more irritable bowel syndrome, migraine headaches, severe menstrual pain, physical and psychological trauma affecting well being, family history of FM, and family pain environment than subjects with IA or controls. Both patient groups had more adult hospitalizations and surgeries than the controls. CONCLUSION: Patients with FM report a high rate of varied pain and adverse experiences throughout life. This real or perceived experience of pain supports the concept that FM is a lifetime disorder of pain processing.