Optimal dose of intrathecal isobaric bupivacaine in total knee arthroplasty.

PURPOSE: Early mobilization is an important aspect of fast-track protocols and intrathecal bupivacaine is often used in primary total knee arthroplasty (TKA). Although the optimal dose is not known, conventional doses leave patients unable to mobilize for two to four hours. The dose of an intrathecally administered local anesthetic should therefore be optimized to achieve immediate postoperative mobilization. This study determined the median effective dose (ED) of intrathecal bupivacaine for primary unilateral TKA. METHODS: Between April 2016 and February 2017 all patients who qualified for unilateral primary TKA were eligible for inclusion. In this dose-finding study, the up-and-down method by Dixon and Massey was used, which is a sequential allocation model. Patients received a dose of isobaric bupivacaine according to the outcome of the preceding patient with an initial starting dose of 5 mg. The dose was increased or decreased by steps of 0.5 mg, depending on the outcome of the preceding patient. During surgery, patients were closely monitored for indications of pain. Time points of regaining motor and sensory functions were determined. RESULTS: Twenty-five patients were included. Mean (SD) age was 70.1 (8.8) yr old, median [IQR] body mass index was 29.5 [27.3-30.9 kg·m-2], and 48% were female. In 11 patients the dose was inadequate; of these, nine patients needed additional anesthesia during surgery, and in four of these nine patients a conversion to general anesthesia was required. The median ED was 3.5 (95% confidence interval [CI], 3.1 to 4.0) mg of intrathecal bupivacaine. The calculated ED50 was 3.4 (95% CI, 2.7 to 4.0) mg; the calculated ED95 was 5 (95% CI, 3.7 to 8.0) mg. CONCLUSION: In this small study with tight control over operative duration, the median effective dosage of intrathecal isobaric bupivacaine for primary unilateral TKA was 3.5 mg and the ED95 was 5 mg. Reduction of conventional dosages of intrathecal bupivacaine is feasible at centres using fast-track arthroplasty protocols.

Optimizing the dose of local infiltration analgesia and gabapentin for total knee arthroplasty, a randomized single blind trial in 128 patients.

BACKGROUND AND PURPOSE: Effective analgesia is essential for postoperative recovery and rehabilitation in TKA. The challenge of analgesic regimes is to obtain adequate pain relief and maximum muscle control to mobilize and rehabilitate patients early. However, the optimal dose and best composition are not known. We hypothesized that there would be no differences in reported postoperative pain on the day of the TKA surgery as well as the first day after surgery when different combinations of ropivacain for LIA and gabapentin are given. METHODS: This prospective randomized trial examined 128 TKA patients treated with LIA and gabapentin in four groups. Group A: 300-mg ropivacain/600-300-300-mg gabapentin. Group B: 150-mg ropivacain/600-300-300-mg gabapentin. Group C: 300-mg ropivacain/300-100-100-mg gabapentin. Group D: 150-mg ropivacain/300-100-100-mg gabapentin. Primary endpoint was pain (NRS) at multiple moments. Secondary endpoints were number of adverse effects, length of hospital stay (LOS), the amount of consumption of pain medication, and wound leakage. Generalized estimating equation (GEE) was used to detect differences between the four groups regarding the course of pain. RESULTS: No differences regarding adverse effects, LOS, and wound leakage were found. GEE revealed a significant difference in course of pain between group A and B, with group B experiencing higher NRS scores postoperatively than group A (p=0.021). No differences between the other groups were found. INTERPRETATION: The results of the current study suggest that LIA with 300-mg (150ml) ropivacain might be more effective than 150-mg (75ml) ropivacain. Alteration in dose of gabapentin appears not to have influence on the course of pain.

Slow delayed rectifier potassium current blockade contributes importantly to drug-induced long QT syndrome.

BACKGROUND: Drug-induced long QT syndrome is generally ascribed to inhibition of the cardiac rapid delayed rectifier potassium current (IKr). Effects on the slow delayed rectifier potassium current (IKs) are less recognized. Triggered by a patient who carried the K422T mutation in KCNQ1 (encoding the α-subunit of the IKs channel), who presented with excessive QT prolongation and high serum levels of norfluoxetine, we investigated the effects of fluoxetine and its metabolite norfluoxetine on IKs. METHODS AND RESULTS: ECG data from mutation carriers and noncarriers revealed that the K422T mutation per se had mild clinical effects. Patch clamp studies, performed on HEK293 cells, showed that heterozygously expressed K422T KCNQ1/KCNE1 channels had a positive shift in voltage dependence of activation and an increase in deactivation rate. Fluoxetine and its metabolite norfluoxetine both inhibited KCNQ1/KCNE1 current, with norfluoxetine being the most potent. Moreover, norfluoxetine increased activation and deactivation rates. Computer simulations of the effects of norfluoxetine on IKs and IKr demonstrated significant action potential prolongation, to which IKs block contributed importantly. Although the effects of the mutation per se were small, additional IKs blockade by norfluoxetine resulted in more prominent QTc prolongation in mutation carriers than in noncarriers, demonstrating synergistic effects of innate and drug-induced IKs blockade on QTc prolongation. CONCLUSIONS: IKs blockade contributes importantly to drug-induced long QT syndrome, especially when repolarization reserve is reduced. Drug safety tests might have to include screening for IKs blockade.

Sudden cardiac arrest associated with use of a non-cardiac drug that reduces cardiac excitability: evidence from bench, bedside, and community.

AIMS: Non-cardiac drugs that impair cardiac repolarization (electrocardiographic QT prolongation) are associated with an increased sudden cardiac arrest (SCA) risk. Emerging evidence suggests that non-cardiac drugs that impair cardiac depolarization and excitability (electrocardiographic QRS prolongation) also increase the risk for SCA. Nortriptyline, which blocks the SCN5A-encoded cardiac sodium channel, may exemplify such drugs. We aimed to study whether nortriptyline increases the risk for SCA, and to establish the underlying mechanisms. METHODS AND RESULTS: We studied QRS durations during rest/exercise in an index patient who experienced ventricular tachycardia during exercise while using nortriptyline, and compared them with those of 55 controls with/without nortriptyline and 24 controls with Brugada syndrome (BrS) without nortriptyline, who carried an SCN5A mutation. We performed molecular-genetic (exon-trapping) and functional (patch-clamp) experiments to unravel the mechanisms of QRS prolongation by nortriptyline and the SCN5A mutation found in the index patient. We conducted a prospective community-based study among 944 victims of ECG-documented SCA and 4354-matched controls to determine the risk for SCA associated with nortriptyline use. Multiple mechanisms may act in concert to increase the risk for SCA during nortriptyline use. Pharmacological (nortriptyline), genetic (loss-of-function SCN5A mutation), and/or functional (sodium channel inactivation at fast heart rates) factors conspire to reduce the cardiac sodium current and increase the risk for SCA. Nortriptyline use in the community was associated with a 4.5-fold increase in the risk for SCA [adjusted OR: 4.5 (95% CI: 1.1-19.5)], particularly when other sodium channel-blocking factors were present. CONCLUSIONS: Nortriptyline increases the risk for SCA in the general population, particularly in the presence of genetic and/or non-genetic factors that decrease cardiac excitability by blocking the cardiac sodium channel.

In-hospital cardiac arrest is associated with use of non-antiarrhythmic QTc-prolonging drugs.

AIMS: QTc interval-prolonging drugs have been linked to cardiac arrhythmias, cardiac arrest and sudden death. In this study we aimed to quantify the risk of cardiac arrest associated with the use of non-antiarrhythmic QTc-prolonging drugs in an academic hospital setting. METHODS: We performed a case-control study in which patients, for whom intervention of the advanced life support resuscitation team was requested for cardiac arrest between 1995 and 2003 in the Academic Medical Centre, Amsterdam, were compared with controls regarding current use of non-antiarrhythmic QTc-prolonging drugs. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression, adjusting for potential confounding factors. RESULTS: A statistically significant increased risk of cardiac arrest (OR 2.1, 95% CI 1.2, 3.5) was observed in patients who received QTc-prolonging drugs (42/140). The risk was more pronounced in patients receiving doses > 1 defined daily dose (OR 2.5, 95% CI 1.1, 5.9), patients taking > 1 QTc-prolonging drug simultaneously (OR 4.8, 95% CI 1.6, 14) and patients taking pharmacokinetic interacting drugs concomitantly (OR 4.0, 95% CI 1.2, 13). CONCLUSIONS: Use of non-antiarrhythmic QTc-prolonging drugs in hospitalized patients with several underlying disease is associated with an increased risk of cardiac arrest. The effect is dose related and pharmacokinetic drug-drug interactions increase the risk substantially. Physicians caring for inpatients should be made aware of the fact that these non-antiarrhythmic drugs may be hazardous, so that potential risks can be weighed against treatment benefits and additional cardiac surveillance can be requested, if necessary.

Clinical relevance of drug-drug interactions : a structured assessment procedure.

INTRODUCTION: Computerised drug interaction surveillance systems (CIS) may be helpful in detecting clinically significant drug interactions. Experience with CIS reveals that they often yield alerts with questionable clinical significance, fail to provide relevant information on risk factors for the adverse reaction of the interaction and fail to detect all significant drug interactions. These problems highlight the importance of transparency and selectivity in choosing the drug interactions to be included in CIS. In The Netherlands, the Working Group on Pharmacotherapy and Drug Information is responsible for maintenance of the CIS of the Royal Dutch Association for the Advancement of Pharmacy (KNMP). METHODS: The Working Group developed an evidence-based procedure for structured assessment of drug-drug interactions and revised all drug interactions in the CIS accordingly. RESULTS: For every drug interaction four core parameters were assessed: (i) evidence on the interaction; (ii) clinical relevance of the potential adverse reaction resulting from the interaction; (iii) risk factors identifying patient, medication or disease characteristics for which the interaction is of special importance; and (iv) the incidence of the adverse reaction. On the basis of this assessment the drug-drug interactions for inclusion in the CIS were selected. After revision of the drug combinations in the KNMP-CIS, the Working Group judged 22% of the combinations to be not interacting and another 12% to be interacting but not requiring action. On the basis of this assessment the subset of drug combinations for which interaction alerts are generated and the information on management of a drug interaction alert for users of the CIS were adapted. When an alert is generated by the CIS, the user of the system is supplied with comprehensive information on the four core parameters, the mechanism of the interaction and critical information for management of the interaction for the individual patient. DISCUSSION: This structured procedure offers the possibility for transparent and reproducible assessment of the clinical relevance of drug interactions. CONCLUSION: A CIS selectively generating interaction alerts based on this assessment may help in realising the goal of good clinical practice and may offer a methodology to further increase drug safety.