Acute Cytokine Response During Breast Cancer Surgery: Potential Role of Dexamethasone and Lidocaine and Relationship with Postoperative Pain and Complications - Analysis of Three Pooled Pilot Randomized Controlled Trials.

PURPOSE: An imbalance in perioperative cytokine response may cause acute pain and postoperative complications. Anesthetic drugs modulate this cytokine response, but their role in non-major breast cancer surgery is unclear. In an exploratory study, we investigated whether intravenous lidocaine and dexamethasone could modulate the cytokine response into an anti-inflammatory direction. We also evaluated interrelationships between cytokine levels, pain scores and postoperative complications. Our goal is to develop multimodal analgesia regimens optimizing outcome after breast cancer surgery. PATIENTS AND METHODS: Forty-eight patients undergoing a lumpectomy were randomly assigned to placebo or lidocaine (1.5 mg⋅kg-1 followed by 2 mg⋅kg-1⋅hour-1) supplemented by dexamethasone zero, 4 or 8 mg, yielding six groups of eight patients. Interleukin (IL)-1ß, IL-1Ra, IL-6, IL-10 levels and pain scores were measured at baseline and four hours postoperatively. We assessed postoperative complications occurring within 30 days. We noted persistent pain and infections as potential immune-related complications (PIRC). We used multiple regression to disentangle the effects of the individual study drugs (given by their partial regression coefficients (b)). Odds ratios (OR) estimated the link between pain scores and complications. RESULTS: Dexamethasone 8 mg increased IL-10 (b=12.70 (95% CI=8.06-17.34), P<0.001). Dexamethasone 4 mg and 8 mg decreased the ratio IL-6/IL-10 (b=-2.60 (-3.93 to -1.26), P<0.001 and b=-3.59 (-5.04 to -2.13), P<0.001, respectively). We could not show modulatory effects of lidocaine on cytokines. High pain scores were linked to the occurrence of PIRC's (OR=2.028 (1.134-3.628), P=0.017). Cytokine levels were not related either to acute pain or PIRC. CONCLUSION: Dexamethasone modulated the perioperative cytokine response into an anti-inflammatory direction. An overall lidocaine effect was not found. Patients with higher pain scores suffered from more 30-day PIRCs. Cytokine levels were not associated with pain or more postoperative complications, even not with PIRC. Larger studies in breast cancer surgery are needed to confirm these explorative results.

Cardiac output-guided hemodynamic therapy for adult living donor kidney transplantation in children under 20 kg: A pilot study.

BACKGROUND: A living-donor (adult) kidney transplantation in young children requires an increased cardiac output to maintain adequate perfusion of the relatively large kidney. To achieve this, protocols commonly advise liberal fluid administration guided by high target central venous pressure. Such therapy may lead to good renal outcomes, but the risk of tissue edema is substantial. AIMS: We aimed to evaluate the safety and feasibility of the transpulmonary thermodilution technique to measure cardiac output in pediatric recipients. The second aim was to evaluate whether a cardiac output-guided hemodynamic therapy algorithm could induce less liberal fluid administration, while preserving good renal results and achieving increased target cardiac output and blood pressure. METHODS: In twelve consecutive recipients, cardiac output was measured with transpulmonary thermodilution (PiCCO device, Pulsion). The algorithm steered administration of fluids, norepinephrine and dobutamine. Hemodynamic values were obtained before, during and after transplantation. Results are given as mean (SD) [minimum-maximum]. RESULTS: Age and weight of recipients was 3.2 (0.97) [1.6-4.9] yr and 14.1 (2.4) [10.4-18] kg, respectively. No complications related to cardiac output monitoring occurred. After transplantation, cardiac index increased with 31% (95% CI = 15%-48%). Extravascular lung water and central venous pressure did not change. Fluids given decreased from 158 [124-191] mL kg-1 in the first 2 patients to 80 (18) [44-106] mL kg-1 in the last 10 patients. The latter amount was 23 mL kg-1 less (95% CI = 6-40 mL kg-1 ) than in one recent study, but similar to that in another. After reperfusion, all patients received norepinephrine (maximum dose 0.45 (0.3) [0.1-0.9] mcg kg-1  min-1 ). Patient and graft survivals were 100% with excellent kidney function at 6 months post-transplantation. CONCLUSION: Transpulmonary thermodilution-cardiac output monitoring appeared to be safe and feasible. Using the cardiac output-guided algorithm led to excellent renal results with a trend toward less fluids in favor of norepinephrine.

Relationship Between Postoperative Pain and Overall 30-Day Complications in a Broad Surgical Population: An Observational Study.

OBJECTIVE: The aim of this study was to establish the relationship between postoperative pain and 30-day postoperative complications. BACKGROUND: Only scarce data are available on the association between postoperative pain and a broad range of postoperative complications in a large heterogeneous surgical population. METHODS: Having postoperative pain was assessed in 2 ways: the movement-evoked pain score on the Numerical Rating Scale (NRS-MEP) and the patients' opinion whether the pain was acceptable or not. Outcome was the presence of a complication within 30 days after surgery. We used binary logistic regression for the total population and homogeneous subgroups to control for case complexity. Results for homogeneous subgroups were summarized in a meta-analysis using inverse variance weighting. RESULTS: In 1014 patients, 55% experienced moderate-to-severe pain on the first postoperative day. The overall complication rate was 34%. The proportion of patients experiencing postoperative complications increased from 0.25 [95% confidence interval (CI) = 0.21-0.31] for NRS-MEP = 0 to 0.45 (95% CI = 0.36-0.55) for NRS-MEP = 10. Patients who found their pain unacceptable had more complications (adjusted odds ratio = 2.17 (95% CI = 1.51-3.10; P < 0.001)). Summary effect sizes obtained with homogeneous groups were similar to those obtained from the total population who underwent very different types of surgery. CONCLUSIONS: Higher actual postoperative pain scores and unacceptable pain, even on the first postoperative day, are associated with more postoperative complications. Our findings provide important support for the centrality of personalized analgesia in modern perioperative care.

Moving beyond pain scores: Multidimensional pain assessment is essential for adequate pain management after surgery.

BACKGROUND: Clinical experience teaches us that patients are willing to accept postoperative pain, despite high pain intensity scores. Nevertheless, relationships between pain scores and other methods of pain assessment, e.g. acceptability of pain or its interference with physical functioning, are not fully established. Our aims were to examine these relationships. METHODS: A cross-sectional study was conducted on patients who underwent major surgery between January 2008 and August 2013. Using logistic regression, we quantified the relationships between movement-evoked pain scores on the numerical rating scale (NRS-MEP) and three dichotomous dependent variables: patient's opinion on acceptability of pain (PO: acceptable or unacceptable pain); nurses' observation of patient's performance of necessary activities to expedite recovery (NO: good or bad performance); a compound measure judging the presence of the clinically desirable situation of acceptable pain associated with good patients' performance (PONO: present or not). Using Receiver Operating Characteristics (ROC) analysis, NRS cut-off points were determined such that they best discriminate between patients having one versus the other outcome for PO, NO and PONO. RESULTS: 15,394 assessments were obtained in 9,082 patients in the first three postoperative days. Nine percent of the patients had unacceptable pain while having an NRS-MEP of 0-4. An estimated 47% (95%CI = 45%-49%) of patients with an NRS-MEP of 7 described their pain as acceptable on day one. Moreover, 33% (31%-35%) performed all required physical activities, and 22% (21%-24%) combined acceptable pain with appropriate movement. NRS cut-off points for PO, NO and PONO were five, four and four, respectively, but had insufficient discriminatory power. CONCLUSIONS: Our results suggest pain management should be guided by the many dimensions of the patient's pain experience, not solely by NRS cut-off points. Future research should evaluate the impact of such multidimensional pain assessment on patients' functional outcome.

Decoding motor responses from the EEG during altered states of consciousness induced by propofol.

OBJECTIVE: Patients undergoing general anesthesia may awaken and become aware of the surgical procedure. Due to neuromuscular blocking agents, patients could be conscious yet unable to move. Using brain-computer interface (BCI) technology, it may be possible to detect movement attempts from the EEG. However, it is unknown how an anesthetic influences the brain response to motor tasks. APPROACH: We tested the offline classification performance of a movement-based BCI in 12 healthy subjects at two effect-site concentrations of propofol. For each subject a second classifier was trained on the subject's data obtained before sedation, then tested on the data obtained during sedation ('transfer classification'). MAIN RESULTS: At concentration 0.5 µg ml(-1), despite an overall propofol EEG effect, the mean single trial classification accuracy was 85% (95% CI 81%-89%), and 83% (79%-88%) for the transfer classification. At 1.0 µg ml(-1), the accuracies were 81% (76%-86%), and 72% (66%-79%), respectively. At the highest propofol concentration for four subjects, unlike the remaining subjects, the movement-related brain response had been largely diminished, and the transfer classification accuracy was not significantly above chance. These subjects showed a slower and more erratic task response, indicating an altered state of consciousness distinct from that of the other subjects. SIGNIFICANCE: The results show the potential of using a BCI to detect intra-operative awareness and justify further development of this paradigm. At the same time, the relationship between motor responses and consciousness and its clinical relevance for intraoperative awareness requires further investigation.

Detection of attempted movement from the EEG during neuromuscular block: proof of principle study in awake volunteers.

Brain-Computer Interfaces (BCIs) have the potential to detect intraoperative awareness during general anaesthesia. Traditionally, BCI research is aimed at establishing or improving communication and control for patients with permanent paralysis. Patients experiencing intraoperative awareness also lack the means to communicate after administration of a neuromuscular blocker, but may attempt to move. This study evaluates the principle of detecting attempted movements from the electroencephalogram (EEG) during local temporary neuromuscular blockade. EEG was obtained from four healthy volunteers making 3-second hand movements, both before and after local administration of rocuronium in one isolated forearm. Using offline classification analysis we investigated whether the attempted movements the participants made during paralysis could be distinguished from the periods when they did not move or attempt to move. Attempted movement trials were correctly identified in 81 (68-94)% (mean (95% CI)) and 84 (74-93)% of the cases using 30 and 9 EEG channels, respectively. Similar accuracies were obtained when training the classifier on the participants' actual movements. These results provide proof of the principle that a BCI can detect movement attempts during neuromuscular blockade. Based on this, in the future a BCI may serve as a communication channel between a patient under general anaesthesia and the anaesthesiologist.

Towards a novel monitor of intraoperative awareness: selecting paradigm settings for a movement-based brain-computer interface.

During 0.1-0.2% of operations with general anesthesia, patients become aware during surgery. Unfortunately, pharmacologically paralyzed patients cannot seek attention by moving. Their attempted movements may however induce detectable EEG changes over the motor cortex. Here, methods from the area of movement-based brain-computer interfacing are proposed as a novel direction in anesthesia monitoring. Optimal settings for development of such a paradigm are studied to allow for a clinically feasible system. A classifier was trained on recorded EEG data of ten healthy non-anesthetized participants executing 3-second movement tasks. Extensive analysis was performed on this data to obtain an optimal EEG channel set and optimal features for use in a movement detection paradigm. EEG during movement could be distinguished from EEG during non-movement with very high accuracy. After a short calibration session, an average classification rate of 92% was obtained using nine EEG channels over the motor cortex, combined movement and post-movement signals, a frequency resolution of 4 Hz and a frequency range of 8-24 Hz. Using Monte Carlo simulation and a simple decision making paradigm, this translated into a probability of 99% of true positive movement detection within the first two and a half minutes after movement onset. A very low mean false positive rate of <0.01% was obtained. The current results corroborate the feasibility of detecting movement-related EEG signals, bearing in mind the clinical demands for use during surgery. Based on these results further clinical testing can be initiated.