Environmental and genetic factors associated with morphine response in the postoperative period.

OBJECTIVE: The aim of this study was to investigate the respective influence of genetic and nongenetic factors on morphine dose requirements and adverse effects after colorectal surgery. METHODS: Seventy-four patients who planned to undergo colorectal surgery were included in this pilot study. The cumulative 24-hour postoperative dose of morphine and postoperative nausea or vomiting requiring the antiemetic ondansetron were the 2 clinical end points. The association of patient characteristics, A118G mu-opioid receptor (OPRM1) single-nucleotide polymorphism (SNP); T802C uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7) SNP; and 2 adenosine triphosphate-binding cassette, subfamily B, member 1 (ABCB1) (multidrug resistance 1 [MDR1]) exonic SNPs (G2677T/A and C3435T) with study end points was investigated. RESULTS: Age, creatinine clearance, and the regular use of psychotropic agents were found to be significantly associated with postoperative morphine dose requirements by univariate analysis. Multivariate analysis identified that age (P = .01) and the use of psychotropic agents before surgery (P = .03) were positively associated with a higher rate of morphine consumption. A higher weight (P = .05) and the ABCB1 homozygous GG-CC diplotype (P = .03) were significantly associated with fewer morphine side effects by univariate analysis. The homozygous ABCB1 diplotype (GG-CC) conferred an odds ratio of 0.12 (95% confidence interval, 0.01-0.98) with regard to the use of ondansetron for postoperative nausea or vomiting. Multivariate analysis identified that the ABCB1 GG-CC diplotype was the only borderline-significant (P = .07) predictive factor of morphine side effects. CONCLUSION: Age and prior use of psychotropic agents are associated with postoperative morphine dose requirements. Whether ABCB1 polymorphisms might predict morphine side effects remains to be determined.

Postoperative analgesia and recovery course after major colorectal surgery in elderly patients: a randomized comparison between intrathecal morphine and intravenous PCA morphine.

BACKGROUND AND OBJECTIVES: Intrathecal morphine is a widely used method for postoperative pain relief after major abdominal surgery. The aim of this randomized, double-blinded study was to compare intrathecal morphine and intravenous PCA morphine for postoperative analgesia and recovery course after major colorectal surgery in elderly patients. METHODS: After written informed consent, patients >70 years of age were prospectively and randomly assigned to receive either preoperative intrathecal morphine (0.3 mg) and postoperative patient-controlled (PCA) intravenous morphine (IT morphine) or PCA alone (group control). Results are presented as mean +/- SD (95% confidence interval). RESULTS: Twenty-six patients successfully completed the study in each group. In the IT morphine group, rate of awakening was delayed. Pain intensity and daily intravenous morphine consumption were significantly reduced 1 and 2 days after surgery in the IT morphine group (P < .01). Mental function (assessed by Mini Mental State and Digit Symbol Substitution Test) was similar in both groups. Episodes of postoperative delirium/confusion occurred similarly in both groups. Time to ileus resolution and time to ambulation without assistance did not differ between the 2 groups. The duration of hospitalization was 8.4 +/- 1.7 (7-11) days and 7.9 +/- 2.0 (6-9.9) days for control and IT morphine, respectively (nonstatistical difference). Patients in the IT morphine group had longer time to awakening from anesthesia and experienced more sedation. CONCLUSIONS: Intrathecal morphine, as compared with intravenous PCA morphine alone, improves immediate postoperative pain and reduces parenteral morphine consumption but does not improve postoperative recovery in elderly patients after major colorectal surgery.

The liability of the anaesthesiologist in ambulatory surgery.

With the development of ambulatory surgery, there may be questions about the legal risk of this procedure. Indeed, the discharge of the patient from the hospital on the same day as the medical treatment raises the problem of monitoring and supervising potential complications, with a substantial delay in medical care, and the anaesthesiologists can be confronted with new areas of liability. This article specifies the French statutory and legal framework of the ambulatory surgery, and shows how the responsibility of the anaesthesiologist can be involved during patient care at all steps. The analysis of judicial precedent shows that the legal risk for the anaesthesiologist also exists in outpatient surgery. Surgery and anaesthesia are medical procedures involving a relatively high risk of damage for the patient. The damage can be attributed to malpractice from one or several health care professionals or to a medical complication (abnormal damage not related to malpractice and independent of past medical history of the patient). In the light of the ongoing and significant development in ambulatory surgery, there may be questions about the legal risk of this procedure. Indeed, the discharge of the patient from the hospital on the same day as the medical treatment raises the problem of monitoring and supervising potential complications, with a substantial delay in medical care. If the patient suffers any damage, the surgeon, the anaesthesiologist and in some cases, the hospital will have to answer in courts: the surgeon for the surgical procedure, the anaesthesiologist for the medical care and the hospital as the liable institution. After having specified the statutory framework of ambulatory surgery, we will see how the responsibility of the anaesthesiologist can be involved during patient care at all steps.

Hospital audit of delayed transfusion after orthopaedic surgery.

BACKGROUND AND OBJECTIVES: To understand the mechanisms related to both the onset and correction of severe anaemia after orthopaedic surgery, we analysed all the full blood counts (FBCs) for patients on one orthopaedic ward during a one-year period in an academic hospital. METHODS: FBCs were screened and the medical records of those patients for whom a postoperative haemoglobin (Hb) concentration below 8 g/dL was recorded at least once were reviewed. The onset of postoperative anaemia was determined by calculating the various time intervals delineated by surgery, the time at which the transfusion threshold was reached and the time at which the lowest Hb level (nadir) and transfusion (if any) occurred. RESULTS: A total of 6573 FBCs drawn from 1255 patients were screened. The medical records of 74 consecutive patients with at least one Hb value < 8 g/dL were analysed. The postoperative Hb nadir was 7.4 (± 0.6) g/dL (mean - SD). The medians (IQR 25-75) of the calculated intervals were: (surgery - nadir): 72 (48-144) h, (nadir - transfusion): 7 (5-21) h and (transfusion threshold - transfusion): 26 (11-51) h. CONCLUSIONS: Delayed transfusion (defined as > 12 hours between the time at which the transfusion threshold was reached and actual transfusion) was observed in 57% of severely anaemic patients after orthopaedic surgery.

Cost-effectiveness of propofol anesthesia using target-controlled infusion compared with a standard regimen using desflurane.

The cost-effectiveness of propofol anesthesia using target-controlled infusion (TCI) versus a standard regimen using desflurane for anesthesia maintenance was analyzed. This observational study consisted of 100 inpatients 18 to 75 years old with an American Society of Anesthesiologists physical status of I or II who were scheduled for otological surgery lasting less than four hours. Patients received one of two treatments. The desflurane-maintenance group received propofol 2-4 mg/kg and sufentanil 0.15-0.30 microg (as the citrate)/kg. A constant fresh gas flow of 1 L/min was used during maintenance of anesthesia. The propofol-maintenance group received TCI propofol and an additional infusion of sufentanil. Anesthesia was induced with 0.15-0.30 microg/kg. One blinded evaluator assessed the postoperative recovery from anesthesia for all patients. The cost of drugs and medical devices used during the intraoperative and postoperative periods was calculated. Effectiveness was defined as the absence of postoperative nausea and vomiting (PONV), while the cost-effectiveness of each procedure was the cost per PONV-free episode. The efficiency of each procedure represented the production of effectiveness per dollar invested. Chi-square and t tests, sensitivity analysis, and logistic regression were also performed. The only intergroup difference detected was the frequency of PONV occurring in the early recovery phase (11 in the desflurane group versus 2 in the propofol group). Of those patients requiring antiemetic rescue, 9 were in the desflurane group and only 2 were in the propofol group (p < 0.05). The TCI propofol regimen was more expensive than the desflurane regimen ($45 versus $28 per patient, respectively) (p < 0.001). The differential cost-effectiveness ratio was $94.7 per PONV-free episode. PONV 24 hours after surgery and patient satisfaction were similar between groups. A standard regimen of desflurane was more cost-effective than TCI propofol for anesthesia maintenance in achieving PONV-free episodes.

[Preliminary results from the SFAR-iNSERM inquiry on anaesthesia-related deaths in France: mortality rates have fallen ten-fold over the past two decades]. / Premiers résultats de l'enquête SFAR-iNSERM sur la mortalité imputable à l'anesthésie en France: reduction par 10 du taux de ces décès en 20 ans.

A National Confidential Inquiry was conducted among death certificators and anaesthetists. A sample of 3700 death certificates from the year 1999 were randomised, after selection of words relating to anaesthesia, surgery, obstetrics, endoscopy, procedural complications, and violent death, with different ratios according to the words and the age; 500 additional certificates relating to deaths in hospital were evaluated to verify the exhaustive nature of the mention of procedures in the certificates. The certificator was sent a simplified form each time the role of the procedure in death could not be excluded (response rate 97%). The anaesthetist was offered a peer review whenever the role of the anaesthetic procedure could not be ruled out (uptake rate 97%). An expert committee analysed the (anonymized) files to determinate the mechanism of the accident and its relationship to anaesthesia. The mortality rates were estimated from the 1996 "Anaesthesia in France" survey. The annual rates of deaths that were totally or partially related to anaesthesia were respectively 7 (CI95%: 2-12) and 47 (31-63) per million. These mortality rates increased with comorbidity, from 4 per million in patients of ASA physical status class 1 to 554 per million in class 4. Similarly, these rates increased with age, from 7 per million in patients less than 45 years old, to 32 in older patients. Most accidents were of ventilatory (38%: airway management: 6%, aspiration pneumonitis: 9%), cardiac (31%: ischaemia: 25%, including anaemia-related), and vascular origin (30%: hemorrhage: 12%, vasodilation by spinal anaesthesia: 6%, anaphylaxis: 3%). The main surgical procedures involved were orthopaedic (50%: hip fracture, haemorrhagic surgery) and digestive (24%: occlusion, peritonitis). INSERM had previously collected data on complications associated with anaesthesia between 1978 and 1982: the annual rates of deaths that were totally or partially related to anaesthesia were respectively 76 and 263 per million. Compared to these previous data, the anaesthesia-related mortality rate fell ten-fold over the last two decades, while the number of anaesthetic procedures at least doubled. In addition, the number of procedures involving old people and patients with poor physical status was multiplied by four. It seems logical to attribute these results to safety and practice guidelines published after the previous inquiry. Progress remains to be made: the present rate of 1/145000 will serve as a basis for systematic analysis of accidents.

Parietal analgesia decreases postoperative diaphragm dysfunction induced by abdominal surgery: a physiologic study.

BACKGROUND AND OBJECTIVES: The postoperative analgesic strategy may influence the magnitude of the postoperative diaphragmatic dysfunction (PODD) induced by abdominal surgery. The purpose of this physiologic study was to evaluate the effect of continuous preperitoneal wound infusion (CPWI) of ropivacaine on PODD after open colorectal surgery. METHODS: Twenty patients with American Society of Anesthesiologists physical status I or II undergoing open colorectal surgery were prospectively included during 2 consecutive 2-month periods. During the first period, we evaluated 10 consecutive patients who received conventional parenteral analgesia (intravenously administered morphine via patient-controlled analgesia and acetaminophen) without parietal analgesia (control group). These patients were compared with 10 consecutive patients who received conventional parenteral analgesia along with parietal analgesia using CPWI of 0.2% ropivacaine at 10 mL/hr for 48 hrs (CPWI group). Diaphragmatic function was assessed preoperatively and at 24 and 48 hrs postoperatively using the sniff nasal inspiratory pressure test (Psniff). Supplemental intravenously administered morphine boluses were administered as needed before Psniff assessments in the control group to reduce differences in pain intensity. RESULTS: Demographic and surgical data did not differ between the 2 groups, nor did preoperative Psniff values (71 cm H2O [SD, 20 cm H2O] vs 65 cm H2O [SD,15 cm H2O] in the control and CPWI groups, respectively). Postoperative Psniff was significantly decreased in the 2 groups, but the reduction was significantly greater in the control group than in the CPWI group both at 24 hrs (-58% [SD, 18%] vs -24% [SD, 19%]; P = 0.001) and at 48 hrs (-44% [SD, 31%] vs -11% [SD, 32%]; P = 0.027). CONCLUSIONS: Parietal analgesia delivered via a CPWI of ropivacaine reduces PODD induced by open colorectal surgery.

Prominent contribution of portal mesenchymal cells to liver fibrosis in ischemic and obstructive cholestatic injuries.

Liver fibrosis is produced by myofibroblasts of different origins. In culture models, rat myofibroblasts derived from hepatic stellate cells (HSCs) and from periductal portal mesenchymal cells, show distinct proliferative and immunophenotypic evolutive profiles, in particular regarding desmin microfilament (overexpressed vs shut-down, respectively). Here, we examined the contributions of both cell types, in two rat models of cholestatic injury, arterial liver ischemia and bile duct ligation (BDL). Serum and (immuno)histochemical hepatic analyses were performed at different time points (2 days, 1, 2 and 6 weeks) after injury induction. Cholestatic liver injury, as attested by serum biochemical tests, was moderate/resolutive in ischemia vs severe and sustained in BDL. Spatio-temporal and morphometric analyses of cytokeratin-19 and Sirius red stainings showed that in both models, fibrosis accumulated around reactive bile ductules, with a significant correlation between the progression rates of fibrosis and of the ductular reaction (both higher in BDL). After 6 weeks, fibrosis was stabilized and did not exceed F2 (METAVIR) in arterial ischemia, whereas micronodular cirrhosis (F4) was established in BDL. Immuno-analyses of alpha-smooth muscle actin and desmin expression profiles showed that intralobular HSCs underwent early phenotypic changes marked by desmin overexpression in both models and that the accumulation of fibrosis coincided with that of alpha-SMA-labeled myofibroblasts around portal/septal ductular structures. With the exception of desmin-positive myofibroblasts located at the portal/septal-lobular interface at early stages, and of myofibroblastic HSCs detected together with fine lobular septa in BDL cirrhotic liver, the vast majority of myofibroblasts were desmin-negative. These findings suggest that both in resolutive and sustained cholestatic injury, fibrosis is produced by myofibroblasts that derive predominantly from portal/periportal mesenchymal cells. While HSCs massively undergo phenotypic changes marked by desmin overexpression, a minority fully converts into matrix-producing myofibroblasts, at sites, which however may be important in the healing process that circumscribes wounded hepatocytes.

Hypoxia-induced changes in the expression of rat hepatobiliary transporter genes.

Cholestatic disorders may arise from liver ischemia (e.g., in liver transplantation) through various mechanisms. We have examined the potential of hypoxia to induce changes in the expression of hepatobiliary transporter genes. In a model of arterial liver ischemia subsequent to complete arterial deprivation of the rat liver, the mRNA levels of VEGF, a hypoxia-inducible gene, were increased fivefold after 24 h. The pattern of VEGF-induced expression and ultrastructural changes, including swelling of the endoplasmic reticulum, indicated that hypoxia affected primarily cholangiocytes, but also hepatocytes, predominantly in the periportal area. Serum and bile analyses demonstrated liver dysfunction of cholestatic type with reduced bile acid biliary excretion. Fluorescence-labeled ursodeoxycholic acid used as a tracer displayed no regurgitation, eliminating bile leakage as a significant mechanism of cholestasis in this model. In liver tissue, a marked reduction in the mRNA levels of Na(+)-taurocholate-cotransporting polypeptide (Ntcp), bile salt export protein (Bsep), and multidrug resistance-associated protein 2 (Mrp2) and an increase in those of Cftr were detected before bile duct proliferation occurred. In cultured hepatocytes, a nontoxic hypoxic treatment caused a decrease in the mRNA and protein expression of Ntcp, Bsep, and Mrp2 and in the mRNA levels of nuclear factors involved in the transactivation of these genes, i.e., HNF4alpha, RXRalpha, and FXR. In bile duct preparations, hypoxic treatment elicited an increase in Cftr transcripts, along with a rise in cAMP, a major regulator of Cftr expression and function. In conclusion, hypoxia triggers a downregulation of hepatocellular transporters, which may contribute to cholestasis, whereas Cftr, which drives secretion in cholangiocytes, is upregulated.

Continuous preperitoneal infusion of ropivacaine provides effective analgesia and accelerates recovery after colorectal surgery: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Blockade of parietal nociceptive afferents by the use of continuous wound infiltration with local anesthetics may be beneficial in a multimodal approach to postoperative pain management after major surgery. The role of continuous preperitoneal infusion of ropivacaine for pain relief and postoperative recovery after open colorectal resections was evaluated in a randomized, double-blinded, placebo-controlled trial. METHODS: After obtaining written informed consents, a multiholed wound catheter was placed by the surgeon in the preperitoneal space at the end of surgery in patients scheduled to undergo elective open colorectal resection by midline incision. They were thereafter randomly assigned to receive through the catheter either 0.2% ropivacaine (10-ml bolus followed by an infusion of 10 ml/h during 48 h) or the same protocol with 0.9% NaCl. In addition, all patients received patient-controlled intravenous morphine analgesia. RESULTS: Twenty-one patients were evaluated in each group. Compared with preperitoneal saline, ropivacaine infusion reduced morphine consumption during the first 72 h and improved pain relief at rest during 12 h and while coughing during 48 h. Sleep quality was also better during the first two postoperative nights. Time to recovery of bowel function (74 +/- 19 vs. 105 +/- 54 h; P = 0.02) and duration of hospital stay (115 +/- 25 vs. 147 +/- 53 h; P = 0.02) were significantly reduced in the ropivacaine group. Ropivacaine plasma concentrations remained below the level of toxicity. No side effects were observed. CONCLUSIONS: Continuous preperitoneal administration of 0.2% ropivacaine at 10 ml/h during 48 h after open colorectal resection reduced morphine consumption, improved pain relief, and accelerated postoperative recovery.

Survey of anesthesia-related mortality in France.

BACKGROUND: This study describes a nationwide survey that estimates the number and characteristics of anesthesia-related deaths for the year 1999. METHODS: Death certificates from the French national mortality database were selected from the International Classification of Diseases, Ninth Revision codes using a variable sampling fraction. Medical certifiers were sent a questionnaire (response rate, 97%), and the anesthesiologist in charge was offered a peer review (acceptance rate, 97%). Files were reviewed to determine the mechanism of each perioperative death and its relation to anesthesia. Mortality rates were calculated using the number of anesthetic procedures estimated from a national 1996 survey and compared with a previous (1978-1982) nationwide study. RESULTS: Among the 4,200 certificates analyzed, 256 led to a detailed evaluation. The death rates totally or partially related to anesthesia for 1999 were 0.69 in 100,000 (95% confidence interval, 0.22-1.2 in 100,000) and 4.7 in 100,000 (3.1-6.3 in 100,000), respectively. The death rate increased from 0.4 to 55 in 100,000 for American Society of Anesthesiologists physical status I and IV patients, respectively. Rates increased with increasing age. Although concerns regarding aspiration of gastric contents remain, intraoperative hypotension and anemia associated with postoperative ischemic complications were the associated factors most often encountered. Deviations from standard practice and organizational failure were often found to be associated with death. CONCLUSION: In comparison with data from a previous nationwide study (1978-1982), the anesthesia-related mortality rate in France seems to be reduced 10-fold in 1999. Much remains to be done to improve compliance of physicians to standard practice and to improve the anesthetic system process.

Inguinal herniorrhaphy under monitored anesthesia care with ilioinguinal-iliohypogastric block: the impact of adding clonidine to ropivacaine.

There is no information concerning the association of ropivacaine and clonidine for ilioinguinal-iliohypogastric block. In this prospective, double-blind study, we randomly assigned 40 adult patients scheduled for inguinal herniorrhaphy under monitored anesthesia care to receive either 225 mg ropivacaine (7.5 mg/mL) alone (control group) or combined with 75 mug clonidine (clonidine group) for preoperative ilioinguinal-iliohypogastric block. After completion of surgery, patients were transferred to the postanesthesia care unit and were asked to stand up and walk around at the second postoperative hour. After leaving the postanesthesia care unit, patients could take oral propacetamol (500 mg) and codeine (30 mg) on request. Pain intensity was assessed with a 100 mm visual analog scale. Time to first request of supplemental analgesics (median [95% confidence interval]) was 10 h (7.1-14.5 h) and 9 h (6.4->24 h) respectively in the clonidine and control groups (P = 0.83). Pain at rest did not differ between groups whereas pain at motion was reduced on the third postoperative day in the clonidine group. More patients who received clonidine experienced orthostatic hypotension upon standing up within the first postoperative hours (6 of 20 versus 1 of 20 in the control group; P < 0.05). In conclusion, the benefit of adding clonidine 75 mug to ropivacaine for ilioinguinal-iliohypogastric block for motion pain on the third postoperative day must be balanced with an increasing risk of orthostatic hypotension in the immediate postoperative period.

Adaptative bile duct proliferative response in experimental bile duct ischemia.

BACKGROUND/AIMS: A rat model of bile duct ischemia was established and used to examine the potential of bile duct proliferation to provide an adaptative response in cholestatic disorders. METHODS: Rats underwent partial or complete arterial deprivation of the liver. Serum biochemical tests, histological analyses and bile secretion measurements were performed at different time points up to 6 weeks after surgery. RESULTS: Rats developed biochemical signs of cholestasis exclusively after complete arterial deprivation. Within 4h, cholangiocytes in these rats showed morphological signs of cell damage. After 48h, they displayed VEGF expression and became proliferative. The proportion of Ki67-labeled cholangiocytes ( approximately 30%) was similar in interlobular bile ducts and periportal ductules. A ductular reaction made of well-formed bile ducts confined to portal tracts developed within 1 week. Bile flow which was initially decreased, was restored at 3 weeks, while the biochemical signs of cholestasis completely resolved at 6 weeks. At this time, the number of bile duct sections was maximal. Fibrosis intensity was also maximal, although moderate (