Peripherally applied opioids for postoperative pain: evidence of an analgesic effect? A systematic review and meta-analysis.

BACKGROUND: Opioids applied peripherally at the site of surgery may produce postoperative analgesia with few side effects. We performed this systematic review to evaluate the analgesic effect of peripherally applied opioids for acute postoperative pain. METHODS: We searched PubMed (1966 to June 2013), Embase (1980 to June 2013), and the Cochrane Central Register of Controlled Trials (The Cochrane Library 2013, Issue 6). Randomized controlled trials investigating the postoperative analgesic effect of peripherally applied opioids vs. systemic opioids or placebo, measured by pain intensity scores, consumption of supplemental analgesics and time to first analgesic were included. Trials with sample sizes of fewer than 10 patients per treatment group or trials with opioids administered intra-articularly or as peripheral nerve blocks were excluded. RESULTS: Data from 26 studies, including 1531 patients and 13 different surgical interventions were included. Clinical heterogeneity of the studies was substantial. Meta-analysis indicated statistically significant, but not clinically relevant, reductions in VAS score at 6-8 h (mean difference -4 mm, 95% CI: -6 to -2) and 12 h postoperatively (mean difference -5 mm, 95% CI: -7 to -3) for peripherally applied opioids vs. placebo and statistically significant increased time to first analgesic (mean difference 153 min, 95% CI: 41-265). When preoperative inflammation was reported (five studies), peripherally applied opioids significantly improved postoperative analgesia. CONCLUSION: Evidence of a clinically relevant analgesic effect of peripherally applied opioids for acute postoperative pain is lacking. The analgesic effect of peripherally applied opioids may depend on the presence of preoperative inflammation.

Intraoperative transfusion threshold and tissue oxygenation: a randomised trial.

BACKGROUND AND OBJECTIVES: Transfusion with allogeneic red blood cells (RBCs) may be needed to maintain oxygen delivery during major surgery, but the appropriate haemoglobin (Hb) concentration threshold has not been well established. We hypothesised that a higher level of Hb would be associated with improved subcutaneous oxygen tension during major spinal surgery. MATERIALS AND METHODS: Fifty patients aged 18 years or older scheduled for spinal fusion with instrumentation were included and randomised to receive RBCs at either a Hb concentration of 7·3 g dL(-1) (restrictive group) or a Hb concentration of 8·9 g dL(-1) (liberal group) (Registration no.: H-C-2009-072). Oxygen tension was measured with a polarographic electrode placed subcutaneously over the left deltoid muscle. The primary endpoint was subcutaneous oxygen tension at the time most patients were still undergoing surgery. RESULTS: Forty-eight patients were included in the intention-to-treat analysis; 25 patients in the restrictive group and 23 patients in the liberal group. The median change in subcutaneous oxygen tension 60 min after surgical incision was -0·79 and -0·75 kPa in the restrictive and the liberal groups, respectively (P = 0·78). No significant difference was found in the lowest subcutaneous oxygen tension; -2·07 vs. -1·95 kPa in the restrictive and the liberal groups, respectively (P = 0·85). CONCLUSION: A Hb concentration transfusion threshold of 8·9 g dL(-1) was not associated with a higher subcutaneous oxygen tension during major spinal surgery than a threshold of 7·3 g dL(-1), but the trial was compromised by methodological difficulties.

Stuck long-term indwelling central venous catheters in adolescents: three cases and a short topical review.

We present three cases of fixated vascular injection ports. Two patients had cystic fibrosis and one had an immunological defect. All catheters were made from polyurethane and implanted in adolescent patients. Indwelling time were 6-8 years. One patient's catheter was entirely integrated in the vessel wall and impossible to remove. In the other two cases, catheters were removed with great difficulty by the interventional radiologists. These cases raise important questions concerning the maximum indwelling time and the choice of catheter material when implanting permanent central venous catheters (CVCs) in adolescents. Furthermore, it highlights the importance of not breaking a CVC in the attempt to remove it.

Depth of anaesthesia monitoring in obese patients: a randomized study of propofol-remifentanil.

BACKGROUND: In obese patients, depth of anaesthesia monitoring could be useful in titrating intravenous anaesthetics. We hypothesized that depth of anaesthesia monitoring would reduce recovery time and use of anaesthetics in obese patients receiving propofol and remifentanil. METHODS: We investigated 38 patients with a body mass index >or=30 kg/m(2) scheduled for an abdominal hysterectomy. Patients were randomized to either titration of propofol and remifentanil according to a cerebral state monitor (CSM group) or according to usual clinical criteria (control group). The primary end point was time to eye opening and this was assessed by a blinded observer. RESULTS: Time to eye opening was 11.8 min in the CSM group vs. 13.4 min in the control group (P=0.58). The average infusion rate for propofol was a median of 516 vs. 617 mg/h (P=0.24) and for remifentanil 2393 vs. 2708 microg/h (P=0.04). During surgery, when the cerebral state index was continuously between 40 and 60, the corresponding optimal propofol infusion rate was 10 mg/kg/h based on ideal body weight. CONCLUSION: No significant reduction in time to eye opening could be demonstrated when a CSM was used to titrate propofol and remifentanil in obese patients undergoing a hysterectomy. A significant reduction in remifentanil consumption was found.

An experimental randomized study of six different ventilatory modes in a piglet model with normal lungs.

A randomized study of 6 ventilatory modes was made in 7 piglets with normal lungs. Using a Servo HFV 970 (prototype system) and a Servo ventilator 900 C the ventilatory modes examined were as follows: SV-20V, i.e. volume-controlled intermittent positive-pressure ventilation (IPPV); SV-20VIosc, i.e. volume-controlled ventilation (IPPV) with superimposed inspiratory oscillations; and SV-20VEf, i.e. volume-controlled ventilation (IPPV) with expiratory flush of fresh gas; HFV-60 denotes low-compressive high-frequency positive-pressure ventilation (HFPPV) and HVF-20 denotes low-compressive volume-controlled intermittent positive-pressure ventilation; and SV-20P denotes pressure-controlled intermittent positive-pressure ventilation. With all modes of ventilation a PEEP of 7.5 cm H2O was used. In the abbreviations used, the number denotes the ventilatory frequency in breaths per minute (bpm). HFV indicates that all gas was delivered via the HFV 970 unit. The ventilatory modes described above were applied randomly for at least 30 min, aiming for a normoventilatory steady state. The HFV-60 and the HFV-20 modes gave lower peak airway pressures, 12-13 cm H2O compared to approximately 17 cm H2O for the other ventilatory modes. Also the mean airway pressures were lower with the HFV modes 8-9 cm H2O compared to 11-14 cm H2O for the other modes. The gas distribution was evaluated by N2 wash-out and a modified lung clearance index. All modes showed N2 wash-out according to a two-compartment model. The SV-20P mode had the fastest wash-out, but the HFV-60 and HFV-20 ventilatory modes also showed a faster N2 wash-out than the others.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoregressive modeling with exogenous input of middle-latency auditory-evoked potentials to measure rapid changes in depth of anesthesia.

Obtaining an adequate depth of anesthesia is a continuous challenge to the anesthetist. With the introduction of muscle-relaxing agents the traditional signs of awareness are often obscured, or difficult to interpret. These signs include blood pressure, heart rate, pupil size, etc. However, these factors do not describe the depth of anesthesia (DA) in a cerebral activity sense. Hence, a better measure of the DA is required. It has been suggested that Auditory-Evoked Potentials (AEP) can provide additional information about the DA. The general method of extracting AEP is by use of a Moving Time Average (MTA). However, the MTA is time consuming because a large number of repetitions is needed to produce an estimate of the AEP. Hence, changes occurring over a small number of sweeps will not be detected by the MTA average. We describe a system-identification method, an autoregressive model with exogeneous input (ARX) model, to produce a sweep-by-sweep estimate of the AEP. The method was clinically evaluated in 10 patients anesthetized with alfentanil and propofol. The time interval between propofol induction and the time when the Na-Pa amplitude was decreased to 25% of the initial amplitude was measured. These measurements showed that ARX-estimated compared to MTA-estimated AEP was significantly faster in tracing transition from consciousness to unconsciousness during propofol induction (p < 0.05).

On-line analysis of AEP and EEG for monitoring depth of anaesthesia.

Achieving and monitoring adequate depth of anaesthesia is a challenge to the anaesthetist. With the introduction of muscle relaxing agents, the traditional signs of awareness are often obscured or difficult to interpret. These signs include blood pressure, heart rate, pupil size, etc. However, these factors do not describe the depth of anaesthesia, (DA), in a cerebral activity sense, hence there is a desire to achieve a better measure of the DA. Auditory Evoked Potentials (AEP) provide two aspects relevant to anaesthesia: (1) they have identifiable anatomical significance and, (2) their characteristics reflect the way in which the brain reacts to a stimulus. However, AEP is embedded in noise from the ongoing EEG background activity. Hence, processing is needed to improve the signal to noise ratio. The methods applied were moving time averaging (MTA) and ARX-modeling. The EEG was collected from the left hemisphere and analysed by FFT to 1 sec epochs and the spectral edge frequency was calculated. Both the changes in ARX extracted AEP and the spectral edge frequency of the EEG correlated well with the time interval between propofol induction and onset of anaesthesia measured by clinical signs (i.e., cessation of eye-lash reflex). The MTA extracted AEP was significantly slower in tracing the transition from consciousness to unconsciousness.

Inhalation of nitric oxide as a treatment of pulmonary hypertension in congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) still has a mortality risk of around 40%. The concomitant pulmonary hypoplasia and the persistent pulmonary hypertension are of major prognostic importance. The use of a selective pulmonary vasodilator may revert this vicious circle that is fatal to many children. Inhalation of nitric oxide (NO) has been suggested as a rational treatment of this condition. The authors report three cases of high-risk infants with CDH where NO was used successfully. It is concluded that hypoxemia in CDH can be treated successfully with NO inhalation when conventional treatment fails, and it may in some cases prove to be an alternative to ECMO.

On-line analysis of middle latency auditory evoked potentials (MLAEP) for monitoring depth of anaesthesia in laboratory rats.

In laboratory animals as well as in human beings a depth of anaesthesia, where the subject has no pain or recall of events from the surgery, should be provided. Haemodynamic parameters such as heart rate and blood pressure are not a guarantee for an optimal depth of anaesthesia, especially when using neuromuscular blocking agents (NMBA). A number of studies suggest that the Middle Latency Auditory Evoked Potentials (MLAEP) contain information about the state of consciousness in humans. The purpose of this study was to examine whether the AEP could serve as an indicator of depth of anaesthesia in rats. The AEP was elicited with a click stimulus and monitored in an 80 ms window synchronised to the stimulus. The AEP was extracted applying an Auto Regressive Model with Exogenous Input (ARX-model) from which a Depth of Anaesthesia Index (DAI) was calculated. DAI was normalised to 100 while awake and decreasing gradually to a level between 50 and 20 as the rat was anaesthetised. Nine rats were anaesthetised and included in the study. Four doses of Hypnorm vet. and Dormicum were given as a total, each with 5 minutes interval. Clinical signs of the level of anaesthesia were observed simultaneously with the AEP. The results showed that in four rats DAI decreased to a level below 30 while anaesthetised. In the remaining five rats the AEP was only decreased to a level below 45. The results indicated that a simple dosing regimen based on weight was unable to give the same depth of anaesthesia in individual rats. The decrease in the DAI correlated well with the loss of stimulus response. In conclusion, MLAEP could be used as an indicator of depth of anaesthesia in rats during Hypnorm vet. and Dormicum administration. However studies applying other anaesthetic drugs should be carried out, before a conclusion of the general utility of the method can be made.

Age-related postoperative morphine requirements in children following major surgery--an assessment using patient-controlled analgesia (PCA).

To investigate if small children require less morphine for postoperative analgesia than do older children and adolescents we analysed the morphine consumption pattern of 28 consecutive children on intravenous patient-controlled analgesia (PCA) following major surgery. The median age-specific morphine requirements between 2 comparable groups of children aged 4-8 years and 9-15 years were compared. We used the Pharmacia-Deltec pump in all children and the same settings: a bolus dose of 25 microgram/kg, an 8 minutes lockout interval and no background infusion. In addition, all children received paracetamol as a supplemently to the morphine. In this study children aged 4-8 years had significantly higher total postoperative morphine requirements compared to children aged 9-15 years, i.e. 11.6 microgram/kg/hour and 7.5 microgram/kg/hour respectively (p = 0.037). Hence, we conclude that children of this age group may have a higher total postoperative morphine requirement following major surgery than older children and adolescents.

Postoperative pain management in children has been improved, but can be further optimized.

The aim of this study is to evaluate the effect of the analgesic treatment currently used in children, and to identify if problems can be related to any particular routine or group of children. Analgesics administered pre-, per- and postoperatively were recorded, and intensity of pain during rest and movement and incidence and severity of side effects were measured four times postoperatively. Fifty-nine children aged 3 to 15 years undergoing miscellaneous operations participated. All children received analgesic treatment. During the study period 26 children reported at least one episode of unacceptable pain, while unacceptable pruritus, nausea or vomiting were observed in 18 children. It was not possible to relate the incidence of pain and side effects to any particular analgesic treatment or type of surgery, but groups of children that might need additional attention were identified. Even though improvements have been obtained, it is still a challenge to optimize the postoperative pain management of children, and when doing so attention should be paid not only to pain relief, but also to side effects of the administered analgesics.

[Postoperative pain relief in children]. / Postoperativ smertebehandling af børn.

Postoperative pain management in children has been subject to increasing interest during the last decade, but is still insufficient. A survey is presented concerning postoperative pain management in children. The value of monitoring the pain as well as the opioid side effects in children is stressed, and such methods are presented. Acute Pain Service is mentioned and the most important pharmacological aspects regarding non-steroidal anti-inflammatory drugs, paracetamol, opioids and local anaesthetics are discussed. The management of postoperative pain in neonates is reviewed separately. It is concluded that the present insufficient management of postoperative pain in children is not due to the lack of methods and techniques, but rather to lack of sufficient utilization and comprehension of the possibilities. Moreover, pain management in children should be individualised. It is also necessary to be more aware of side effects of the pharmacological treatment.

[Patient-controlled analgesia in children]. / Patientkontrolleret smertebehandling af børn.

In order to introduce intravenous patient-controlled analgesia (PCA) in children in the Department of Anaesthesiology and Intensive Care, Odense University Hospital, we evaluated the technique in 13 children following major orthopaedic or abdominal surgery. The pump (Pharmacia-Deltec, CADD-PCA) was loaded with 1 mg/ml morphine in a 50 milliliters cassette. A bolus dose of 25 micrograms/kg and a lock-out interval of eight minutes were the initial settings. The morphine dose used, pain scores and side effects were currently recorded. Ages ranged from 4-15 years (mean 10.5 years) and the method was used for a mean of 89 hours (range 57-144 hours) postoperatively. Morphine requirements averaged 9.5 microgram/kg/hour (range 5.4-15.6 microgram/kg/hour). Pain control was good and side effects were few and of minor nature. PCA is an effective and safe means of providing good quality analgesia in children.

[Sedation and analgesia in ventilator-treated children]. / Sedering og analgesi til børn i respirator.

Ventilator-treated children often require sedation in order to facilitate the ventilation. Sedatives alone or in combination with analgesics are commonly used for this purpose. In some cases, however, the addition of a neuromuscular blocking agent (NMB) may be necessary. In this article a survey is presented regarding both pharmacological and non-pharmacological means of improving the ventilator treatment in ventilated children. The most commonly employed sedatives, opioids and NMB's are discussed. The authors stress that whichever drug is used, it should be administered to the children guided by its effects rather than by a rigid scheme. In that respect monitoring of the treatment is important.

[Persistent pulmonary hypertension in newborn infants]. / Persisterende pulmonal hypertension hos nyfødte.

On the basis of a review of the literature, a survey is presented concerning persistent pulmonary hypertension of the newborn. In this article the authors focus on the pathophysiology, diagnostic criteria and treatment, including mechanical ventilation, pharmacological vasodilation and extracorporal membrane oxygenation. Particular emphasis is placed on the treatment of the condition with inhaled nitric oxide. Nitric oxide is a selective pulmonary vasodilator and able to improve ventilation/ perfusion mismatching in cases where there is an affection of the pulmonary parenchyma. Data from randomized trials with close long-term follow-up is necessary before routine nitrogen oxide treatment can be recommended.

[Nitrogen oxide inhalation in acute pulmonary failure]. / Nitrogenoxidinhalation ved akut lungesvigt.

Two cases of adult respiratory distress syndrome (ARDS) treated successfully with nitric oxide (NO) inhalation are described. One patient had severe sepsis and the other had trauma induced ARDS. The slow entry criteria for extracorporeal membrane oxygenation (ECMO) was fulfilled in both cases. NO inhalation substantially improved oxygenation, reduced pulmonary arterial pressure and peak inspiratory pressure. Treatment with NO inhalation was without side effects and easy to administer through the ventilator. Both patients survived without sequelae. We suggest that inhalation with NO should be tried before ECMO treatment is considered in severe ARDS.

[Incapacitating angina pectoris treated with electric stimulation of the spinal cord]. / Invaliderende angina pectoris behandlet med elektrisk rygmarvsstimulation (ERS).

Thirty patients who had severe incapacitating angina pectoris which had not reacted to the conventional therapeutic measures and which required massive daily opioid consumption were treated with electrical spinal cord stimulation (SCS) by means of a completely implantable stimulation system. The therapeutic effect was good in 87% of the patients who experienced considerably reduced frequency of attacks and markedly reduced opioid consumption (p less than 0.00005). Nine of the patients could reduce opioid consumption and 14 out of 27 could cease their otherwise daily opioid consumption. In four patients, the therapeutic effect was unsatisfactory. In the first 22 patients in whom a unipolar electrode was introduced, displacement of the electrode and subsequent reoperation was a frequent problem. This problem disappeared after change to multipolar electrodes as slight changes in placing of the electrode could easily be compensated for via the external programming equipment. This investigation reveals that SCS is a good therapeutic alternative for this selected patient category.

[Inhalation therapy with nitric oxide--an evaluation of a dosage system and clinical examples]. / Inhalationsbehandling med nitrogenoxyd--evaluering af et doseringssystem og kliniske eksempler på anvendelsen.

In 1987 it was discovered that nitric oxide is a very potent vasodilator and in fact a natural mediator for vasodilatation. The effects of inhalation of nitric oxide on pulmonary vascular resistance were described in 1988 and a new therapeutic possibility for artificially ventilated patients with pulmonary hypertension has arisen. However, the administration of nitric oxide has to be performed with high accuracy and without reaching toxic levels of nitrogendioxide. We have evaluated a system using conventional air and oxygen rotameters for administration of nitric oxide via a ventilator. A comparison of the chemiluminescence technique with a technique based on fuel cells was also performed. With the system it was possible to administer nitric oxide with high accuracy within the range of 10-60 ppm without exceeding values for nitrogendioxide above 0.4 ppm. The analysis of nitric oxide and nitrogendioxide based on electrochemical cells proved to be comparable with the chemiluminescence technique within the same range. Nitric oxide inhalation was used in six patients with severe hypoxia and seemed to have a favorable effect on most of the patients.

[Nitrogen oxide inhalation in critically ill patients]. / Inhaleret nitrogenoxid til kritisk syge patienter.

Inhaled nitric oxide (iNO) has been extensively used in the treatment of severe hypoxaemic respiratory failure and/or pulmonary hypertension. Although the majority of studies have almost consistently demonstrated a beneficial effect on oxygenation and a reduction in pulmonary artery pressures, none of the randomised trials have reported a reduced mortality using iNO on patients with severe respiratory failure. In neonates with severe respiratory failure and pulmonary hypertension, however, iNO can reduce the need of extracorporal membrane oxygenation. Prior to using iNO on adult patients we suggest other measures to be taken (i.e. optimising ventilator settings, ventilation in prone position).