Predicting Unacceptable Pain in Cardiac Surgery Patients Receiving Morphine Maintenance and Rescue Doses: A Model-Based Pharmacokinetic-Pharmacodynamic Analysis.

BACKGROUND: Optimal analgesic treatment following cardiac surgery is crucial for both patient comfort and successful postoperative recovery. While knowledge of both the pharmacokinetics and pharmacodynamics of analgesics is required to predict optimal drug dosing, models quantifying the pharmacodynamics are scarce. Here, we quantify the pharmacodynamics of morphine by modeling the need for rescue morphine to treat unacceptable pain in 118 patients after cardiac surgery. METHODS: The rescue morphine event data were analyzed with repeated time-to-event (RTTE) modeling using NONMEM. Postoperative pain titration protocol consisted of continuous morphine infusions (median duration 20.5 hours) with paracetamol 4 times daily and rescue morphine in case of unacceptable pain (numerical rating scale ≥4). RESULTS: Patients had a median age of 73 years (interquartile range [IQR]: 63-77) and median bodyweight of 80 kg (IQR: 72-90 kg). Most patients (55%) required at least 1 rescue morphine dose. The hazard for rescue morphine following cardiac surgery was found to be significantly influenced by time after surgery, a day/night cycle with a peak at 23:00 (95% confidence interval [CI], 19:35-02:03) each day, and an effect of morphine concentration with 50% hazard reduction at 9.3 ng·mL-1 (95% CI, 6.7-16). CONCLUSIONS: The pharmacodynamics of morphine after cardiac surgery was successfully quantified using RTTE modeling. Future studies can be used to expand the model to better predict morphine's pharmacodynamics on the individual level and to include the pharmacodynamics of other analgesics so that improved postoperative pain treatment protocols can be developed.

Randomized Controlled Trial on the Influence of Intraoperative Remifentanil versus Fentanyl on Acute and Chronic Pain after Cardiac Surgery.

BACKGROUND: Remifentanil has been associated with increased acute and potentially chronic postoperative pain. The objective of this prospective randomized controlled trial was to investigate the influence of intraoperative remifentanil on acute and chronic postoperative pain after cardiac surgery. METHODS: Patients (N = 126) receiving standardized anesthesia with propofol and intermittent intravenous fentanyl at predetermined times for cardiac surgery were randomized to intraoperatively receive either a continuous remifentanil infusion or additional intermittent intraoperative fentanyl as needed. The primary endpoint was chronic thoracic pain at 12 months after surgery. Secondary endpoints were pain at 3 and 6 months after surgery and analgesic requirements and pain levels in the first 72 hours. RESULTS: There was no significant difference in incidence of chronic thoracic pain between the remifentanil and fentanyl groups, respectively (20% vs. 18%; P = 0.817). At 3 months, however, significantly more patients in the remifentanil group reported chronic thoracic pain (51% vs. 33%; P = 0.047). This effect was more pronounced in younger patients and in patients receiving a higher dose of remifentanil (both P < 0.05). The first 24 and 48 hours postoperatively, morphine consumption in the remifentanil group was significantly higher than in the fentanyl group (34.3 mg [interquartile range (IQR) 25.3 to 48.2] vs. 30.2 mg [IQR 19.2 to 38.1], P = 0.028; and 46.8 mg [IQR 33.8 to 59.2] vs. 39.0 mg [IQR 6.2 to 51.4], P = 0.047, respectively). CONCLUSIONS: Intraoperative use of remifentanil during cardiac surgery does not impact chronic postoperative pain 1 year after surgery. Nevertheless, remifentanil increases analgesic requirements and thoracic pain until 3 months after surgery, and its use is therefore less favorable during cardiac surgery.

Morphine Glucuronidation and Elimination in Intensive Care Patients: A Comparison with Healthy Volunteers.

BACKGROUND: Although morphine is used frequently to treat pain in the intensive care unit, its pharmacokinetics has not been adequately quantified in critically ill patients. We evaluated the glucuronidation and elimination clearance of morphine in intensive care patients compared with healthy volunteers based on the morphine and morphine-3-glucuronide (M3G) concentrations. METHODS: A population pharmacokinetic model with covariate analysis was developed with the nonlinear mixed-effects modeling software (NONMEM 7.3). The analysis included 3012 morphine and M3G concentrations from 135 intensive care patients (117 cardiothoracic surgery patients and 18 critically ill patients), who received continuous morphine infusions adapted to individual pain levels, and 622 morphine and M3G concentrations from a previously published study of 20 healthy volunteers, who received an IV bolus of morphine followed by a 1-hour infusion. RESULTS: For morphine, a 3-compartment model best described the data, whereas for M3G, a 1-compartment model fits best. In intensive care patients with a normal creatinine concentration, a decrease of 76% was estimated in M3G clearance compared with healthy subjects, conditional on the M3G volume of distribution being the same in intensive care patients and healthy volunteers. Furthermore, serum creatinine concentration was identified as a covariate for both elimination clearance of M3G in intensive care patients and unchanged morphine clearance in all patients and healthy volunteers. CONCLUSIONS: Under the assumptions in the model, M3G elimination was significantly decreased in intensive care patients when compared with healthy volunteers, which resulted in substantially increased M3G concentrations. Increased M3G levels were even more pronounced in patients with increased serum creatinine levels. Model-based simulations show that, because of the reduction in morphine clearance in intensive care patients with renal failure, a 33% reduction in the maintenance dose would result in morphine serum concentrations equal to those in healthy volunteers and intensive care patients with normal renal function, although M3G concentrations remain increased. Future pharmacodynamic investigations are needed to identify target concentrations in this population, after which final dosing recommendations can be made.

Large variation in anti-factor Xa levels with nadroparin as thromboprophylaxis in COVID-19 and non-COVID-19 critically ill patients.

PURPOSE: Critically ill COVID-19 and non-COVID-19 patients receive thromboprophylaxis with the LMWH nadroparin. Whether a standard dosage is adequate in attaining the target anti-FXa levels (0.20-0.50 IU/ml) in these groups is unknown. METHODS: This study was a prospective, observational study in the ICU of a large general teaching hospital in the Netherlands. COVID-19 and non-COVID-19 patients admitted to the ICU who received LMWH in a prophylactic dosage of 2850 IU, 5700 IU or 11400 IU subcutaneously were eligible for the study. Anti-FXa levels were determined 4 h after administration. Relevant laboratory parameters, prespecified co-variates and clinical data were extracted from the electronic health record system. The primary goal was to evaluate anti-FXa levels in critically ill patients on a prophylactic dosage of nadroparin. The second goal was to investigate whether covariates had an influence on anti-FXa levels. RESULTS: A total of 62 patients were included in the analysis. In the COVID-19 group and non-COVID-19 group, 29 (96%) and 12 patients (38%) reached anti-FXa levels above 0.20 IU/ml, respectively. In the non-COVID-19 group, 63% of the patients had anti-FXA levels below the target range. When adjusted for nadroparin dosage a significant relation was found between body weight and the anti-FXa level (p = 0.013). CONCLUSION: A standard nadroparin dosage of 2850 IU sc in the critically ill patient is not sufficient to attain target anti-FXa levels in the majority of the studied patient group. We suggest a standard higher dosage in combination with body-weight dependent dosing as it leads to better exposure to nadroparin. CLINICAL TRIALS REGISTRATION: Retrospectively registered, ClinicalTrials.gov ID NTC 05926518 g, date of registration 06/01/23, unique ID 2020/1725.

The Val158Met polymorphism of the COMT gene is associated with increased pain sensitivity in morphine-treated patients undergoing a painful procedure after cardiac surgery.

AIMS: The catechol-O-methyltransferase (COMT) Val158Met polymorphism affected pain sensitivity of healthy volunteers upon application of experimental pain stimuli. The relevance of these findings in morphine-treated postoperative cardiac patients undergoing painful healthcare procedures is unknown; therefore, the aim of this study was to investigate whether the COMT Val158Met polymorphism increases pain sensitivity in morphine-treated patients undergoing an unavoidable painful routine procedure after cardiac surgery. METHODS: One hundred and seventeen postoperative cardiac patients in the intensive care unit were genotyped for the COMT Val158Met polymorphism. All patients were treated with continuous morphine infusions for pain at rest, and received a bolus of morphine (2.5 or 7.5 mg) before a painful procedure (turning and/or chest drain removal) on the first postoperative day. Numerical rating scale (NRS) scores were evaluated at the following four time points: at baseline (at rest), and before, during and after the painful procedure. RESULTS: Overall mean NRS scores were significantly higher in patients carrying the Met-variant allele. During the painful procedure, the mean NRS score was significantly higher for Met/Met patients compared with Val/Met and Val/Val patients (mean NRS 3.4 ± 2.8, 2.7 ± 2.4 and 1.7 ± 1.7, respectively; P = 0.04). In Met/Met patients, the increase in NRS scores during the painful procedure compared with the baseline NRS score was clinically relevant (ΔNRS ≥ 1.3) and statistically significant and appeared to be independent of sex and the morphine bolus dose. CONCLUSIONS: Our results show that the COMT Val158Met polymorphism contributes to variability in pain sensitivity after cardiac surgery of morphine-treated patients in the intensive care unit, because Met-allele carriers were more sensitive to overall pain and procedure-related pain.

The use of the Behavioral Pain Scale to assess pain in conscious sedated patients.

BACKGROUND: Assessing pain in mechanically ventilated critically ill patients is a great challenge. There is a need for an adequate pain measurement tool for use in conscious sedated patients because of their questionable communicative abilities. In this study, we evaluated the use of the Behavioral Pain Scale (BPS) in conscious sedated patients in comparison with its use in deeply sedated patients, for whom the BPS was developed. Additionally, in conscious sedated patients, the combination of the BPS and the patient-rated Verbal Rating Scale (VRS-4) was evaluated. METHODS: We performed a prospective evaluation study in 80 nonparalyzed critically ill adult intensive care unit patients. Over 2 mo, nurses performed 175 observation series: 126 in deeply sedated patients and 49 in conscious sedated patients. Each observation series consisted of BPS ratings (range 3-12) at 4 points: at rest, during a nonpainful procedure, at retest rest, and during a routine painful procedure. Patients in the conscious sedated state also self-reported their pain using the 4-point VRS-4. RESULTS: BPS scores during painful procedures were significantly higher than those at rest, both in deeply sedated patients (5.1 [4.8-5.5] vs 3.4 [3.3-3.5], respectively) and conscious sedated patients (5.4 [4.9-5.9] vs 3.8 [3.5-4.1], respectively) (mean [95% confidence interval]). For both groups, scores obtained during the nonpainful procedure and at rest did not significantly differ. There was a strong correlation between nurses' BPS ratings and conscious sedated patients' VRS-4 ratings during the painful procedure (r(s) = 0.67, P < 0.001). At rest and during nonpainful procedures, 98% of the observations were rated as acceptable pain (VRS 1 or 2) by both nurses and patients. During painful procedures, nurses rated the pain higher than patients did in 16% of the observations and lower in 12% of the observations. CONCLUSION: The BPS is a valid tool for measuring pain in conscious sedated patients during painful procedures. Thus, for noncommunicative and mechanically ventilated patients, it may be regarded as a bridge between the observational scale used by nurses and the VRS-4 used by patients who are able to self-report pain.

Improved analgesia after the realisation of a pain management programme in ICU patients after cardiac surgery.

BACKGROUND AND OBJECTIVE: Although clinical guidelines recommend systematic evaluation of pain in ICU patients, we know little about the effects from such systematic pain evaluation. This study aims to quantify the effect of a pain management programme in the ICU. METHODS: In this prospective two-phase study, pain levels scored by ICU patients after cardiac surgery through sternotomy were compared before and after the implementation of a pain management programme. The pain management programme consisted of a three-fold strategy; all staff was trained in assessing pain and in providing adequate analgesia, a new patient data management system obliged nurses to ask patients for their pain score three times a day and the preferred analgesic treatment was optimised. The numeric rating scale (NRS 0-10) was used by 190 patients. A NRS at least 4 was considered unacceptable. A generalised linear mixed-effects model was used for analysing repeated measurements data. RESULTS: The occurrence of unacceptable pain (NRS > or = 4) was significantly lower in the intervention group [odds ratio 2.54 (95% confidence interval 1.22-5.65; P = 0.01) for the control group]. Patients in the intervention group received significantly more morphine (29.3 vs. 22.6 mg a day, P<0.01), with higher morphine amounts administered to patients with higher NRS scores (P = 0.01). In the control group, no such relationship was observed (P = 0.66). There was no difference in length of stay in the ICU or in ventilation time. CONCLUSION: The intervention programme successfully reduced the occurrence of unacceptable pain. Further improvement of pain management should focus on the prevention of pain.

Comparison of different pain scoring systems in critically ill patients in a general ICU.

BACKGROUND: Pain in critically ill patients in the intensive care unit (ICU) is common. However, pain assessment in critically ill patients often is complicated because these patients are unable to communicate effectively. Therefore, we designed a study (a) to determine the inter-rater reliability of the Numerical Rating Scale (NRS) and the Behavioral Pain Scale (BPS), (b) to compare pain scores of different observers and the patient, and (c) to compare NRS, BPS, and the Visual Analog Scale (VAS) for measuring pain in patients in the ICU. METHODS: We performed a prospective observational study in 113 non-paralyzed critically ill patients. The attending nurses, two researchers, and the patient (when possible) obtained 371 independent observation series of NRS, BPS, and VAS. Data analyses were performed on the sample size of patients (n = 113). RESULTS: Inter-rater reliability of the NRS and BPS proved to be adequate (kappa = 0.71 and 0.67, respectively). The level of agreement within one scale point between NRS rated by the patient and NRS scored by attending nurses was 73%. However, high patient scores (NRS > or = 4) were underestimated by nurses (patients 33% versus nurses 18%). In responsive patients, a high correlation between NRS and VAS was found (rs = 0.84, P < 0.001). In ventilated patients, a moderate positive correlation was found between the NRS and the BPS (rs = 0.55, P < 0.001). However, whereas 6% of the observations were NRS of greater than or equal to 4, BPS scores were all very low (median 3.0, range 3.0 to 5.0). CONCLUSION: The different scales show a high reliability, but observer-based evaluation often underestimates the pain, particularly in the case of high NRS values (> or = 4) rated by the patient. Therefore, whenever this is possible, ICU patients should rate their pain. In unresponsive patients, primarily the attending nurse involved in daily care should score the patient's pain. In ventilated patients, the BPS should be used only in conjunction with the NRS nurse to measure pain levels in the absence of painful stimuli.

Is Intraoperative Remifentanil Associated With Acute or Chronic Postoperative Pain After Prolonged Surgery? An Update of the Literature.

OBJECTIVE: Remifentanil is an ultra-short-acting opioid that is used commonly during both short-term and prolonged surgery. This review investigated associations of intraoperative remifentanil administration with acute postoperative pain, hyperalgesia, and chronic postoperative pain, with emphasis on the perioperative coanesthetic drug regimen used. METHODS: Medline and Embase databases were searched for randomized studies, evaluating the intraoperative use of remifentanil (>2 h) versus another analgesic or a different dosage of remifentanil, and reporting acute postoperative pain parameters such as postoperative pain scores, hyperalgesia, acute opioid tolerance, or analgesics requirements. Furthermore, all studies in which remifentanil was used intraoperatively and parameters for chronic postoperative pain were measured were included (pain levels after a prolonged period of time after surgery). RESULTS: From the 21 studies that were identified, less than half of the studies found higher acute postoperative pain, higher postoperative analgesic requirements after intraoperative remifentanil use, or both. Coanesthetics to some extent determined this incidence, with mainly studies using volatile agents reporting increased pain levels. There was less evidence when remifentanil was combined with total intravenous anesthesia or a combination of anesthetics. The limited number of studies (n=4) evaluating chronic pain suggested a potential association with the intraoperative use of remifentanil. DISCUSSION: Although studies are diverse and sample sizes small, coanesthetics used in combination with remifentanil may influence the occurrence of postoperative hyperalgesia. No firm conclusions could be made regarding acute and chronic pain, indicating that further research with the goal to investigate the effect of volatile or intravenous anesthetics along with simultaneous remifentanil infusion on acute and chronic postoperative pain is needed.

Remifentanil versus fentanyl during cardiac surgery on the incidence of chronic thoracic pain (REFLECT): study protocol for a randomized controlled trial.

BACKGROUND: Chronic thoracic pain after cardiac surgery is prevalent (11 to 56%) and may affect patients' physical and mental health status. Despite its favorable pharmacokinetic and pharmacodynamic properties, high doses of remifentanil administered during surgery are reported to cause acute postoperative pain and increased requirements for analgesics. Recently, an association between remifentanil use and the incidence of chronic thoracic pain in the long term was also reported. Our objective is to investigate the influence of the intraoperative remifentanil on chronic postoperative pain in a prospective randomized controlled trial. METHODS/DESIGN: In this prospective, randomized, single-blind clinical trial, all patients (N = 126) between 18 and 85 years undergoing cardiac surgery via sternotomy receive a continuous infusion of propofol together with intermittent intravenous fentanyl at predetermined times perioperatively. Patients are randomized to receive either an additional continuous infusion of remifentanil (0.15 µg(-1)kgIBW(-1) min(-1)) or additional fentanyl (200 to 500 µg) as needed during surgery.The primary end point is the prevalence of chronic thoracic pain 12 months after surgery. Secondary end points include acute postoperative pain; postoperative analgesic use; chronic thoracic pain 3 and 6 months after surgery; quality of life (SF-12) at 3, 6 and 12 months after surgery; work productivity; and use of health care. In addition, thermal detection and pain thresholds are measured preoperatively, 3 days after surgery and 12 months after surgery using quantitative sensory testing (QST). Finally, the influence of several genetic variances on the different outcomes will be measured. DISCUSSION: Chronic thoracic pain is prevalent after cardiac surgery, and research is needed to minimize the risk of chronic persistent postoperative pain, which is an invalidating, long-term complication of surgery. The objective of this trial is to determine the influence of perioperative remifentanil on long-term pain outcomes for cardiac patients in a prospective randomized trial. The results may be used to optimize perioperative analgesia techniques and, thereby, improve quality of life after cardiac surgery. TRIAL REGISTRATION: Clinicaltrials.gov NCT02031016 on 13 December 2013.

Risk factors for chronic thoracic pain after cardiac surgery via sternotomy.

OBJECTIVE: This study examines the influence of patient demographics and peri- and postoperative (<7 days) characteristics on the incidence of chronic thoracic pain 1 year after cardiac surgery. The impact of chronic thoracic pain on daily life is also documented. METHODS: A prospective cohort study of 146 patients admitted to the intensive care unit after cardiac surgery via sternotomy was carried out. Pain scores (numeric rating scale 0-10) were recorded during the first 7 postoperative days. One year later, a questionnaire was used to evaluate the incidence in the 2 preceding weeks of chronic thoracic pain (numeric rating scale >0) associated with the primary surgery. RESULTS: One year after surgery, 42 (35%) of the 120 responding patients reported chronic thoracic pain. Multivariate regression analysis of patient characteristics revealed that non-elective surgery, re-sternotomy, severe pain (numeric rating scale ≥ 4) on the third postoperative day, and female gender were all independent predictors of chronic thoracic pain. In addition, the chronic sufferers reported more sleep disturbances and more frequent use of analgesics than their cohorts. CONCLUSIONS: We have identified a number of factors correlated with persistent thoracic pain following cardiac surgery with sternotomy. Awareness of these predictors may be useful for further research concerning both the prevention and treatment of chronic thoracic pain, thereby potentially ameliorating the postoperative quality of life of a significant proportion of patients. Meanwhile, chronic thoracic pain should be discussed preoperatively with patients at risk so that they are truly informed about possible consequences of the surgery.