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Lignocaine Therapy for Ventricular Ectopic Activity after Acute Myocardial Infarction: A Double-blind Trial
Abstract
The effectiveness of intravenous lignocaine in suppressing ventricular ectopic activity after acute myocardial infarction was examined in a double-blind trial in 82 patients. Whereas suppression of unifocal ventricular ectopics was achieved by lignocaine in 90% of patients, other forms of potentially more dangerous ectopic activity (multifocal or R-on-T ectopics) seemed more resistant to therapy. Cessation of ectopic activity was also observed in about one-third of the patients in the control group. The incidence of ventricular tachycardia and fibrillation and the mortality during and after the trial period were similar in the lignocaine-treated and control groups, whether or not the initial ventricular ectopics had been suppressed.This study provides no evidence to support the routine use of intravenous lignocaine in the management of ventricular ectopic activity after acute myocardial infarction.
... The R-on-T phenomenon, multifocal ventricular extrasystoles and extrasystoles > 5 per minute, double ventricular extrasystoles and bigeminy have all been associated with ventricular fibrillation and ventricular tachycardia (Lown et al., 1967; Lawrie et al., 1968). However, earlier workers have not clearly established the importance of preceding arrhythmias over subsequent arrhythmias and the relative importance of short bursts of ventricular tachycardia, idioventricular rhythm, sustained ventricular tachycardia and ventricular fibrillation (Raftery et al., 1970; Fluck et al., 1967; Chopra et al., 1971). Their studies have not excluded the effects of treatment. ...
... From such a comparison it is clear that the number of ventricular extrasystoles per minute is of little significance and the other parameters are of only limited value. However, from this study and other reports (Chopra et al., 1971; Pentecost and Bennet, 1972), the R-on-T phenomenon frequently presages ventricular tachycardia/fibrillation, although not the other arrhythmias. However, its relative infrequency makes it of limited use. ...
... The author has noted transitions from a fast to a slow ventricular rhythm of similar contour, and vice versa. The criteria used to distinguish these arrhythmias are arbitrary and others have had similar experience using different criteria (Clarke and Hamer, 1974; De Soyza et al., 1974). It has been suggested that ventricular tachycardias after myocardial infarction are usually automatic in the first 28 hr and later may be due to re-entry (Wellens, Lie and Durrer, 1974) and our experience would support this. ...
Ventricular arrhythmias were recorded in 233 patients in a prospective study of patients with acute myocardial infarction. In over 95% of patients antiarrhythmic therapy was not given until the onset of ventricular tachycardia, ventricular fibrillation, or persistent idioventricular rhythm. There was a mortality of 18% during the patients' stay in hospital. The most important features of ventricular ectopic activity, which preceded these severe ventricular arrhythmias in the first 48 hr, were multiformity, variation of coupling intervals of larger or equal to 0-1 sec, the R-on-T phenomenon, double ventricular extrasystoles and ventricular bigeminy. The number of a single ventricular extrasystoles per minute was related to the probability of these severe ventricular arrhythmias but to a lesser degree. It was found that if all the patients with the first two prognostic features that if all the patients with the first two prognostic features were removed, the number of single ventricular extrasystoles was not of significant import and the other features were less important. Three-quarters of the severe arrhythmias occurred in the first 24 hr and during this period 60% were preceded by either multiform ventricular extrasystoles or extrasystoles with variable coupling. The importance of these findings in relation to prophylactic therapy is discussed.
... Additionally, it is well known that lidocaine is hepatically metabolized and then finally leads to liver dysfunction. Some reports have demonstrated that lidocaine is significantly toxic to articular chondrocytes34567. The mechanism of lidocaine chondrotoxicity has been intensively investigated, but the molecular mechanisms underlying this cytotoxic outcome are unclear. ...
We demonstrated that upregulation of both gene expression of endoplasmic reticulum (ER) stress chaperones (BiP, calnexin, calreticulin, and PDI) and ER stress sensors (ATF6, IRE1 and PERK) was induced by lidocaine, a local anesthetic, in PC12 cells. In addition to gene regulation, lidocaine also induced typical ER stress phenomena such as ART6 proteolytic cleavage, eIF2 alpha phosphorylation, and XBP1 mRNA splicing. In in vivo experiments, while lidocaine downregulated gene expression of antiapoptotic factors (Bcl-2 and Bcl-xl), pro-apoptotic factor (Bak and Bax) gene expression was upregulated. Furthermore, lidocaine induced apoptosis, as measured histochemically, and upregulated PARP1, a DNA damage repair enzyme. These results are the first to show that lidocaine induces apoptosis through ER stress in vitro and in vivo.
... The problem of post-infarction arrhythmias resistapt to conventional anti-arrhythmic treatment is a familiar one in the Coronary Care Unit. Lignocaine is one of the most effective suppressive drugs but lignocaine-resistant arrhythmias are by no means uncommon (Chopra el al 1971). Treatment with betareceptor blockers may be limited by hypotensive effects or by a negative inotropic action, diphenylhydantoin depresses left ventricular function, procaineamide may lead to asystole and quinidine may produce syncope or gastro-intestinal side-effects. ...
Disopyramide, a new anti-arrhythmic drug, has been assessed in twenty-one episodes of cardiac arrhythmia secondary to acute ischaemic heart disease which failed to respond to more conventional suppressive therapy with lignocaine and other standard drugs.
The intravenous administration of 100 mg of disopyramide resulted in suppression of two out of seven episodes of supraventricular arrhythmia, and eleven out of fourteen episodes of ventricular arrhythmias. Successful suppression correlated with blood levels of disopyramide in most cases of ventricular arrhythmias but not in the supraventricular arrhythmias.
There were no adverse effects on blood pressure or cardiac function. There were minimal effects on conduction in the electrocardiogram.
It is concluded that disopyramide, which probably acts by direct depression of myocardial irritability, is a useful new anti-arrhythmic drug in acute myocardial infarction, especially in those patients with ventricular arrhythmias resistant to more conventional anti-arrhythmic therapy.
Introduction:
Intravenous lignocaine is an amide local anaesthetic known for its analgesic, antihyperalgesic and anti-inflammatory properties. Administration of intravenous lignocaine has been shown to enhance perioperative recovery parameters. This is the protocol for a systematic review which intends to summarise the evidence base for perioperative intravenous lignocaine administration in patients undergoing spinal surgery.
Methods and analysis:
Our primary outcomes include: postoperative pain scores at rest and movement at predefined early, intermediate and late time points and adverse events. Other outcomes of interest include perioperative opioid consumption, composite morbidity, surgical complications and hospital length of stay. We will include randomised controlled trials, which compared intravenous lignocaine infusion vs standard treatment for perioperative analgesia. We will search electronic databases from inception to present; MEDLINE, EMBASE and Cochrane Library (Cochrane Database of Systematic Reviews and CENTRAL). Two team members will independently screen all citations, full-text articles and abstract data. The individual study risk of bias will be appraised using the Cochrane risk of bias tool. We will obtain a risk ratio or mean difference (MD) from the intervention and control group event rates based on the nature of data. We will correct for the variable measurement tools by using the standardised MD (SMD). We will use a random-effects model to synthesise data. We will conduct five subgroup analysis: major versus minor surgery, emergency versus elective surgery, patients with chronic pain conditions versus patients without, duration of lignocaine infusion and adult versus paediatric. Confidence in cumulative evidence for will be classified according to the Grading of Recommendations, Assessment, Development and Evaluation system. We will construct summary of findings tables supported detailed evidence profile tables for predefined outcomes.
Ethics and dissemination:
Formal ethical approval is not required as primary data will not be collected. The results will be disseminated through a peer-reviewed publication.
Prospero registration number:
CRD420201963314.
Zu Anfang dieses Abschnitts soll mit einem etwas vereinfachenden Schema eine Abgrenzung des morphologischen, funktionellen und klinischen Bereichs der Coronarerkrankungen erfolgen (Abb. 40.1).
The underlying process responsible for the large majority of cases of ischemic heart disease (IHD) is coronary atherosclerosis. This entity, the leading cause of death of American men of middle age, is responsible for more than 600 000 deaths annually in the United States alone [1]. Its manifestations include angina pectoris, congestive heart failure, myocardial infarction, and sudden cardiac death. Approaches to the modification of IHD include primary prevention of atherosclerosis, early intervention to forestall development of symptomatic IHD, and medical and surgical therapy of specific manifestations.
Tachyarrhythmias are common during the first few days following acute myocardial infarction, reflecting the unstable electrical properties of ischemic cardiac cells. In the conventional coronary care unit the control of these tachyarrhythmias by electrical means has usually involved emergency countershock for life-threatening episodes or the occasional use of overdrive pacing. The last decade has seen the emergence and refinement of electrophysiologic techniques allowing intracardiac recording and stimulation including the delivery of intravascular counter-shock. These more invasive techniques have not been widely applied in the setting of acute infarction, but the question arises as to their potential role. This chapter reviews the types of tachyarrhythmias observed in patients during acute myocardial infarction (AMI), and the electrical techniques available for diagnosis and management. The potential usefulness of newer approaches is discussed in the context of evidence from Duke University Medical Center regarding the spectrum of tachyarrhythmias detected in the coronary care unit of the 1980s.
Since their inception in the early 1960s, coronary care units (CCUs) have undoubtedly saved many lives. However, anecdotal experience cannot substitute for a critical analysis of the impact of coronary care units, or for a comparison of the impact to the costs incurred.
Herzrhythmusstörungen stellen eine der häufigsten Komplikationen beim frischen Herzmuskelinfarkt dar (9, 61, 67, 84). Insbesondere die gefürchteten ventrikulären Arrhythmien treten am häufigsten in der Frühphase des frischen Infarktes auf und werden im weiteren Verlauf immer seltener (Abb. 1). Die erste, besonders gefährliche Phase des Infarktes im Hinblick auf Herzrhythmusstörungen läuft normalerweise außerhalb der Klinik ab, so daß die Patienten, die die Inten-siv-Station erreichen, schon eine positive Auslese in dieser Richtung darstellen. Wenn auch die Zeit bis zum Eintreffen im Krankenhaus vielerorts durch Rettungswagensysteme wesentlich verkürzt wurde (75, 79), so stellt sich doch nach wie vor die Frage, wie man die lebensbedrohlichen tachykarden Rhythmusstörungen in der Praehospitalphase verhindern kann. Hierzu gibt es bisher noch keine wirklich befriedigende Lösung.
In diesem Kapitel soll die Pharmakologie des Chinidins und ähnlich wirkender Pharmaka besprochen werden. Chinidin kann die meisten Herzarrhythmien unterdrücken und stellt damit einen normalen Sinusrhythmus wieder her. Jedoch stehen auch andere Behandlungsmethoden, sowohl mit Pharmaka als auch auf elektrischem Wege, zur Verfügung, damit ist eine Arrhythmiebehandlung mit Chinidin oft nicht die Therapie der Wahl. Selbst wenn Chinidin indiziert ist, wird es nur sehr selten allein verwendet.
Sowohl der Pathologie als auch der Pathophysiologie der koronaren Herzkrankheit im allgemeinen, als auch den entsprechenden Ver?nderungen beim akuten Herzmuskelinfarkt sind in diesem Buch ausf?hrliche Darstellungen gewidmet (s. Kap. 2 und Kap. 3). An dieser Stelle soll nur kurz auf einige Aspekte eingegangen werden, die f?r die Diagnostik, den Verlauf der akuten Erkrankung oder das therapeutische Vorgehen im klinischen Alltag von Bedeutung sind.
Art und Häufigkeit von Rhythmusstörungen nach einem Myokardinfarkt sind für die Überlebensprognose des Patienten entscheidend. Insbesondere die polytopen ventrikulären Extrasystolen, Salven- und R- auf T-Ektopien, die leicht in das Kammerflimmern überleiten, konnten bisher weder durch β-Receptorenblocker noch das häufig benutzte Antiarrhythmikum Lidocain zuverlässig beseitigt werden, und zwar weder beim Infarktpatienten [1, 2, 3, 5, 7] noch bei experimentellem Myokardinfarkt [4, 8, 10].
Herz-Kreislauferkrankungen stehen unter den Todesursachen bei uns an erster Stelle. Soweit Angaben des Statistischen Bundesamtes über die exakte Todesursache überhaupt etwas aussagen können, starben 1976 138 900 Menschen an coronarer Herzkrankheit; 77 700 davon an einem Herzinfarkt. Auf die Problematik solcher Angaben kann hier nicht näher eingegangen werden. Es gehört aber sicher zu den dringlichsten Aufgaben der Inneren Medizin, Prophylaxe, Frühdiagnostik und Soforttherapie dieser Krankheitsgruppe zu verbessern. Bei der Behandlung des akuten Myocardinfarkts konnten in den letzten 10 Jahren durch die Einrichtung coronarer Wachstationen Fortschritte erzielt und die Hospitalletalität auf 10–15% gesenkt werden. Dennoch liegt die Gesamtsterblichkeit bei rund 40%. Wenn man bedenkt, daß sich etwa zwei Drittel der Infarkttodesfälle ereignen, bevor die Patienten die Klinik erreichen (43, 57, 59, 65, 75, 81, 84) so wird deutlich, daß die Ansätze für eine Lösung des Problems nur in der vorklinischen Phase des Myokardinfarkts zu suchen sind. Dies führte zum Konzept der „Precoronary care“, das die Verbesserung der Sofortversorgung des Infakrtpatienten in der Praehospitalphase zum Ziel hat (50).
Lidocaine has been recognized to induce neurotoxicity. However, the molecular mechanism underlying this effect, especially the critical molecules in cells that mediated the lidocaine-induced apoptosis were unclear. In the present study, PC12 cells were administrated with lidocaine for 48h. Using MTT assay and flow cytometry, we found lidocaine significantly decreased the cell proliferation and S phases in PC12 cells with treatment concentrations, and significantly enhanced cell apoptosis with treatment concentrations. Two-dimensional gel electrophoresis (2-DE) analysis and LC-MS/MS were used to identification of protein biomarkers. Six proteins were identified. Among them, three were up-expressed including ANXA6, GNB2 and STMN1, other three were down-expressed including ubiquitin-linke protein 7 (UBL7), DDAH2 and BLVRB. Using qRT-PCR, we confirmed that lidocaine up-regulated the mRNA expression of STMN1, GNB2, ANXA6 and DDAH2, and found that the GNB2 had the largest change (about increased by 6.4 folds). The up-regulation of GNB2 by lidocaine was also validated by western blot. After transfected with 100μM GNB2-Rat-453 siRNA, the expression of GNB2 in PC12 cells was almost completely inhibited; and the cell proliferation and cells in S phases were significantly enhanced, cell apoptosis including both early apoptosis and later apoptosis were significantly reduced in the presence of 0.5mM lidocaine for 48h. Therefore, neuronal apoptosis was induced by lidocaine and this effect was mediated by GNB2. Further research is needed to assess the clinical relevance and exact mechanism of neuronal apoptosis caused by lidocaine.
During the past decade, there has been considerable interest in the value of class I antiarrhythmic drugs for the prevention of ventricular fibrillation during the early hours of acute myocardial infarction. In animal studies a number of such drugs have been shown to prevent ventricular fibrillation following coronary artery ligation (1). However, only lidocaine has been studied extensively in randomized trials of the prevention of ventricular fibrillation in patients with suspected acute myocardial infarction. Eleven such trials (2–12) have been conducted involving a total of 8527 patients. There are only a few trials of the prophylactic effects of other class I drugs such as tocainide (13,14); the total number of patients studied in trials of these agents is too small to allow meaningful conclusions to be drawn about their effectiveness in the prevention of ventricular fibrillation.
Coronary artery disease is a major public health problem affecting both developed and developing countries. Acute coronary syndromes include unstable angina and myocardial infarction with or without ST-segment elevation (electrocardiogram sector is higher than baseline). Ventricular arrhythmia after myocardial infarction is associated with high risk of mortality. The evidence is out of date, and considerable uncertainty remains about the effects of prophylactic use of lidocaine on all-cause mortality, in particular, in patients with suspected myocardial infarction.
To determine the clinical effectiveness and safety of prophylactic lidocaine in preventing death among people with myocardial infarction.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 3), MEDLINE Ovid (1946 to 13 April 2015), EMBASE (1947 to 13 April 2015) and Latin American Caribbean Health Sciences Literature (LILACS) (1986 to 13 April 2015). We also searched Web of Science (1970 to 13 April 2013) and handsearched the reference lists of included papers. We applied no language restriction in the search.
We included randomised controlled trials assessing the effects of prophylactic lidocaine for myocardial infarction. We considered all-cause mortality, cardiac mortality and overall survival at 30 days after myocardial infarction as primary outcomes.
We performed study selection, risk of bias assessment and data extraction in duplicate. We estimated risk ratios (RRs) for dichotomous outcomes and measured statistical heterogeneity using I(2). We used a random-effects model and conducted trial sequential analysis.
We identified 37 randomised controlled trials involving 11,948 participants. These trials compared lidocaine versus placebo or no intervention, disopyramide, mexiletine, tocainide, propafenone, amiodarone, dimethylammonium chloride, aprindine and pirmenol. Overall, trials were underpowered and had high risk of bias. Ninety-seven per cent of trials (36/37) were conducted without an a priori sample size estimation. Ten trials were sponsored by the pharmaceutical industry. Trials were conducted in 17 countries, and intravenous intervention was the most frequent route of administration.In trials involving participants with proven or non-proven acute myocardial infarction, lidocaine versus placebo or no intervention showed no significant differences regarding all-cause mortality (213/5879 (3.62%) vs 199/5848 (3.40%); RR 1.02, 95% CI 0.82 to 1.27; participants = 11727; studies = 18; I(2) = 15%); low-quality evidence), cardiac mortality (69/4184 (1.65%) vs 62/4093 (1.51%); RR 1.03, 95% CI 0.70 to 1.50; participants = 8277; studies = 12; I(2) = 12%; low-quality evidence) and prophylaxis of ventricular fibrillation (76/5128 (1.48%) vs 103/4987 (2.01%); RR 0.78, 95% CI 0.55 to 1.12; participants = 10115; studies = 16; I(2) = 18%; low-quality evidence). In terms of sinus bradycardia, lidocaine effect is imprecise compared with effects of placebo or no intervention (55/1346 (4.08%) vs 49/1203 (4.07%); RR 1.09, 95% CI 0.66 to 1.80; participants = 2549; studies = 8; I(2) = 21%; very low-quality evidence). In trials involving only participants with proven acute myocardial infarction, lidocaine versus placebo or no intervention showed no significant differences in all-cause mortality (148/2747 (5.39%) vs 135/2506 (5.39%); RR 1.01, 95% CI 0.79 to 1.30; participants = 5253; studies = 16; I(2) = 9%; low-quality evidence). No significant differences were noted between lidocaine and any other antiarrhythmic drug in terms of all-cause mortality and ventricular fibrillation. Data on overall survival 30 days after myocardial infarction were not reported. Lidocaine compared with placebo or no intervention increased risk of asystole (35/3393 (1.03%) vs 14/3443 (0.41%); RR 2.32, 95% CI 1.26 to 4.26; participants = 6826; studies = 4; I(2) = 0%; very low-quality evidence) and dizziness/drowsiness (74/1259 (5.88%) vs 16/1274 (1.26%); RR 3.85, 95% CI 2.29 to 6.47; participants = 2533; studies = 6; I(2) = 0%; low-quality evidence). Overall, safety data were poorly reported and adverse events may have been underestimated. Trial sequential analyses suggest that additional trials may not be needed for reliable conclusions to be drawn regarding these outcomes.
This Cochrane review found evidence of low quality to suggest that prophylactic lidocaine has very little or no effect on mortality or ventricular fibrillation in people with acute myocardial infarction. The safety profile is unclear. This conclusion is based on randomised controlled trials with high risk of bias. However (disregarding the risk of bias), trial sequential analysis suggests that additional trials may not be needed to disprove an intervention effect of 20% relative risk reduction. Smaller risk reductions might require additional higher trials.
Classifications of antiarrhythmic drugs have developed because of a need to organise the large number of agents available according to pharmacological properties of clinical relevance. The current classification is a hybrid of classification systems developed in the early 1970s. It subdivides drugs according to 4 major pharmacological actions: (a) depression of phase 0 sodium current; (b) antagonism of adrenergic effects on the heart; (c) prolongation of action potential duration; and (d) calcium channel blockade. Further subdivision of sodium channel blockers is based on the kinetics of sodium channel blockade and drug effects on action potential duration. A critical analysis of selected aspects of the clinical actions of antiarrhythmic drugs indicates the value of the current classification, as well as some limitations in its ability to separate drugs into distinct groups with characteristic clinical properties. The strengths of the current classification are due to the clinical importance of the pharmacological properties on which it is based. These result in electrophysiological actions, indications, and adverse effects that are typical for each group of drugs. The limitations of the current system relate to the propensity of individual drugs to have actions of more than one class simultaneously, the way that the various actions of a given drug are dependent on concentration, rate, and tissue type, and to problems in subclass definition.
Tachyarrhythmias are due to abnormalities of impulse formation — focus genesis—, or impulse conduction — facilitating reentry — or the combination of both. Antiarrhythmic drugs counteract these two fundamental disturbances. According to their main effect on electrophysiological properties of the action potential, antiarrhythmic agents in therapeutic concentrations may be divided into 4 groups. In man the influence of antiarrhythmic drugs on the different parts of intracardiac conduction system allows to establishing indications and contraindications. Until now, the effect of these drugs on the diseased human heart has not been investigated sufficiently; for this reason, the clinical therapy is based on empiricism, i.e., a systematic therapeutic approach. The most effective antiarrhythmic drugs hereby got preferred indications. Under clinical conditions one can evaluate the pathogenesis of rhythm disturbances by analysing the therapeutical effects of drugs with specific electrophysiological properties, e.g. by the response to calcium antagonists — type Verapamil — which act specifically to the so called slow response action potentials. Preexisting TU-abnormality in the ECG indicates inhomogenous repolarisation as a pre-requisite for ventricular reentry tachycardia. The acute myocardial infarction causes changing electrophysiological pre-requisites for the development of arrhythmias and therefore it seems to be unlikely to achieve therapeutic effects by a single antiarrhythmic drug. During hospitalization it is useful to treat the patient with a sufficiently high dosis of Lidocain, but during pre-hospitalization, without intensive care, this is more doubtful. After the phase of hospitalization, the prophylactic treatment with beta-blocking drugs can decrease by about one half the risk of sudden heart death. A consequent antiarrhythmic treatment is also necessary for other risk patients who are suffering from ventricular arrhythmias.
The acute electrophysiologic effects of a bolus injection of 100 mg. of lidocaine were investigated in 39 patients with impulse formation and conduction defects by means of His-bundle recording and were correlated with plasma lidocaine levels. The effects of therapeutic plasma levels on conduction intervals and refractory periods were subsequently studied during sinus rhythm and atrial pacing. The sinus-node function was studied by measurement of the sino-atrial recovery time. Seventeen patients had conduction defects in or distal to the His bundle, six exclusively proximal to the His bundle, and nine at both levels. Nine patients had pre-existent sinus-node malfunction. Ten out of 39 patients suffered from acute myocardial infarction. Two patients were studied twice because of changed A-V conduction. Intravenous injection of 100 mg. of lidocaine within 20 seconds produced peak arterial plasma levels (mean 26.6 mug per milliliter) 60 seconds after the beginning of the injection. Seven out of 26 patients showed transient progression of their pre-existent infra-His conduction impairment, coincident with peak plasma levels, apparently due to drug toxicity. Even at therapeutic plasma levels, five out of 26 patients showed decremental intraventricular conduction during atrial pacing when compared to control tracings. His-Purkinje refractoriness was not shortened in these patients and increased in two. Lidocaine had no effect on ventricular automaticity in three patients with complete heart block. Lidocaine had no consistent effects on sinus rate, SART, atrial refractoriness, or A-V nodal conduction as measured by pooled AH intervals and the Wenckebach point, and on A-V nodal refractoriness. It is concluded that lidocaine is safe in patients with high degrees of A-V nodal block and in patients with impulse formation disturbances. However, patients with intraventricular conduction defects are prone to deterioration of their conduction disturbance due to drug toxicity. The drug should be given to such patients preferably if monitoring and pacemaker facilities are available and by the intramuscular route to avoid peak plasma levels.
The concept of two different types of extrasystoles, parasystolic and coupled, depends upon two distinguishing characteristics of these beats. The characteristics of the parasystolic extrasystoles are the invariability of the ectopic cycle together with their independence from the basic rhythm. Coupled extrasystoles demonstrate a dependence upon the basic rhythm although they may express some degree of ectopic variability. The degree of variation of the interectopic interval or its common denominator measures the irregularity of the ectopic parasystolic rhythm. The variation of coupling intervals describes the dependence of the ectopic beat upon the basic rhythm. In a study of 719 electrocardiograms with ventricular extrasystoles, about one-third of the extrasystoles appeared intermediate between these types since they had both variable coupling intervals and variable interectopic intervals. Some of these had total variability of coupling intervals and of the interectopic intervals (random non-parasystolic coupling), and others had limited variation of coupling intervals when expressed in relationship to the total duration of electrical diastole (approximate non-parasystolic coupling). Both these ectopic types appeared to be associated with cardiac disease, and repetitive ventricular extrasystoles. Left bundle branch type extra-with fixed coupling. There were no obvious relationships between the contour and the type of coupling of ventricular extrasystoles. Left bundle branch type extrasystoles with vertical or right axis were the most frequent, particularly in normal subjects, but in the presence of cardiac disease there were more electrocardiograms with right bundle branch type extrasystoles. Extrasystoles in the presence of underlying conduction defects were usually of opposite configuration to this defect. The contour of uniform extrasystoles did not appear to predispose to serious ventricular arrhythmias but multiformity of extrasystoles was an important prognostic indicator. It is suggested that variability of contour and coupling are important signs of inhomogenous conduction and may precede the onset of severe ventricular arrhythmias. Random nonparasystolic coupling and marked multiformity indicate a more sinister arrhythmic state.
Uniform ventricular extrasystoles can be divided into three types: fixed coupling, parasystole, and variable non-parasystolic coupling. Frequency distributions of coupling intervals of ventricular extrasystoles were determined from long electrocardiographic recordings of 51 patients with variable coupling. These distributions were of five types: (a) two distinct coupling intervals, (b) a preponderance of extrasystoles with short coupling intervals and less frequent extrasystoles with progressively longer coupling, (c) a preponderance of long coupling intervals and less frequent extrasystoles with progressively shorter coupling, (d) an even distribution and (3) a central distribution. Interectopic intervals were measured in these electrocardiograms (ECGs). Parasystole was found only in three recordings. It is recommended that the diagnosis of parasystole be made only if the degree of variation of the ectopic cycle (both when it is manifest and when it is concealed) is less than the variation of the coupling intervals. When the ECGs with variable non-parasystolic coupling were compared with 44 ECGs with fixed coupling, it was found that variable coupling was associated with abnormalities of the basic electrocardiographic contour, multiformity of extrasystoles and repetitive extrasystoles.
Intravenous disopyramide was used in 13 patients who developed recurrent ventricular dysrhythmias despite initial treatment with intravenous lignocaine after admission to the Coronary Care Unit of a busy district hospital. This was effective in 8 of the 13 patients treated and there was no major side effects observed. Disopyramide has the advantage of being available both as an oral and an intravenous preparation and is a useful drug to be added to the list of more conventional anti-dysrhythmic agents.
Lignocaine is widely used as a local anaesthetic and antiarrhythmic drug. It is commonly administered to patients with acute myocardial infarction as prophylaxis for ventricular fibrillation, although its efficacy in preventing primary ventricular fibrillation is still debated. Toxicity, sometimes with serious clinical consequence, is not uncommon and is usually related to overdosage. Blood lignocaine concentrations correlate roughly with antiarrhythmic and toxic effects and might be useful as an end point for monitoring prophylactic therapy.
Administration of lignocaine as a local anaesthetic may result in blood lignocaine concentration in the antiarrhythmic or even toxic ranges. Expected peak levels for various routes of local anaesthesia are tabulated so that ‘safe’ total doses can be calculated. Intramuscular injection of high doses results in sustained therapeutic levels but is often associated with early minor toxicity.
Lignocaine is eliminated primarily by hepatic metabolism, which appears to be limited by liver perfusion. Active metabolites may contribute to therapeutic and/or toxic effects. Disease states such as cardiac failure or drugs that alter hepatic blood flow may significantly affect lignocaine clearance.
Pharmacokinetic studies in man show wide variability in drug disposition between patients, even when cardiac and hepatic status is considered, making specific dosing recommendations a problem. With intravenous injection, multicompartment kinetics is observed, with an initial rapid decline phase and initial decline in antiarrhythmic activity due to redistribution. With constant infusion, steady state concentrations of lignocaine are seen after 3 to 4 hours in normal subjects and after 8 to 10 hours in patients with myocardial infarction without circulatory insufficiency. In patients with cardiac failure, blood lignocaine concentration may continue to rise for 24 to 48 hours. In the presence of cardiac failure, decreased volumes of distribution and clearance require reduction in loading and maintenance doses. Lignocaine clearance is reduced in patients with liver disease and appears to be a sensitive index of liver dysfunction. A dosing algorithm for treatment of patients with myocardial infarction is presented.
Patients with suspected or proven acute myocardial infarction complicated by ventricular arrhythmias not corrected by lidocaine therapy (bolus dose 100 mg followed by infusion 2 mg/min) were treated either with an increased dose of lidocaine (bolus dose 50 mg followed by infusion 3 mg/min) or with 600 mg N,N-bis dimethylammonium chloride (QX-572, Astra, Sweden) as an i.v. infusion during 30 min (3 patients) or 60 min (13 patients). In the lidocaine group the arrhythmias were controlled in 6 out of 15 patients, in the QZ-572 group in 12 out of 16, a difference that is not statistically significant. However, the frequency of side-effects was significantly higher (p less than 0.001) in the QX-572 group (15 out of 16 patients). They were also more severe, including pronounced tachycardia and hypertension. It is concluded that despite the high antiarrhythmic effect of QX-572, an increase of the lidocaine dose would be safer and preferable in the clinical situation studied.
Primary ventricular fibrillation (PVF) occurs in approximately 3--10% of uncomplicated acute myocardial infarction (AMI) patients. The major reason for this variability in incidence appears to be population diferences in the time from symptom onset to admission. Other risk factors have not been consistently shown to influence the risk of PVF. Warning arrhythmias do not warn of impending PVF in from 20--80% of AMI patients; thus, antiarrhythmic therapy reserved for those with warning arrhythmias may fail to prevent PVF in a significant number of patients. Although a review of 13 controlled trials of lidocaine prophylaxis shows only two suggesting a protective effect from this drug, only one study was free of major defects in trial design. This trial showed a striking decrease in PVF incidence when lidocaine was employed. Lidocaine should probably be administered to all uncomplicated AMI patients during the first 48 hours after infarction. Its utility in preventing ventricular fibrillation in complicated AMI patients and in the very early AMI period is unclear.
Early investigators suggested that ventricular fibrillation without heart failure in acute myocardial infarction was reliably preceded by warning arrhythmias, and that suppression of such arrhythmias with intravenous lidocaine could avoid the need for resuscitation. While the efficacy and safety of lidocaine have been substantiated, the reliability of warning arrhythmias as predictors for primary ventricular fibrillation has not. We present data showing that the risk of primary ventricular fibrillation is most dependent on the patient's age and the interval since the onset of his symptoms, rather than on the presence of warning arrhythmias. We have estimated that lidocaine prophylaxis would have to be given to about 12 patients in the highest risk group (patients under age 50 and within six hours of the onset of symptoms), compared to about 400 patients in the lowest risk group (patients above age 70 and more than 24 hours since the onset of symptoms), to prevent one episode of primary ventricular fibrillation in each group. We propose that these risk stratifications, as adapted to the conditions in specific hospitals, provide the most rational approach to lidocaine prophylaxis of primary ventricular fibrillation.
Twenty-six patients with clinically significant ventricular arrhythmias were randomly assigned to treatment with either intravenous disopyramide or lidocaine; crossover to the other agent was permitted in nine cases of primary drug failure. In addition, disopyramide was administered nonrandomly to seven patients with ventricular arrhythmias not controlled by lidocaine in standard doses. Arrhythmia control (greater than 50 percent reduction of premature ventricular complexes) was achieved in all 22 trials with disopyramide and in 9 of 13 trails with lidocaine in the random study, whereas clinical efficacy (arrhythmia control with absence of side effects) occurred respectively in 15 of 22, and 8 of 13 trials. In all 11 patients (7 nonrandom, 4 random) whose arrhythmia was not controlled with lidocaine the arrhythmia was controlled with disopyramide. Thus, the clinical efficacy of intravenous disopyramide ran parallel to that of lidocaine in patients with ventricular arrhythmias. Furthermore, intravenous disopyramide was an effective alternative agent for patients with arrhythmia not controlled by lidocaine.
All patients in the San Pedro and Peninsula Hospital suspected of having a myocardial infarction are routinely given an initial bolus injection of 75 mg of lidocaine and concomitant constant infusion. Those who continue to exhibit serious ventricular ectopy are subjected to a precise treatment protocol employing 50 mg bolus injections of lidocaine every 5 minutes, if necessary, to a total of 225 mg. The clinical success of this treatment program in 1,000 consecutive patients with acute myocardial infarction prompted more extensive study of lidocaine kinetics in 23 patients receiving lidocaine with the multiple bolus technique. Plasma lidocaine levels were determined 1, 3 and 5 minutes after an initial 75 mg bolus injection and after three subsequent 50 mg bolus injections given at 5 minute intervals. The mean peak plasma concentration was 2.3 μg/ml, and no level exceeded 4.8 μg/ml. Save for a single plasma value of 1.1 μg, 5 minutes after the initial 75 mg bolus dose, the mean plasma levels were within the accepted therapeutic range at all times.The effect of clinical left ventricular failure on plasma lidocaine levels and drug distribution was examined. Although plasma levels 1 minute after the first bolus injection were 1.0 ± 0.2 and 2.0 ± 0.4 μgml (mean ± standard error of the mean) in class 0–1 and class II-III heart failure, respectively (P < 0.05), mean concentrations were not significantly different (P < 0.2) 5 minutes after the last bolus dose. A dosage schedule employing multiple bolus injections of lidocaine every 5 minutes, if ventricular extrasystoles are not controlled, to a total of 225 mg over 16 minutes provides adequate blood levels, results in no significant toxicity and may be safely employed with excellent results in patients with infarction irrespective of the presence of moderate congestive heart failure.
Twenty patients with frequent ventricular ectopic beats had a 5 1/2 hour ECG rhythm strip recorded. Individual patients showed a marked spontaneous variability from one half-hour to the next in the total number of ectopic beats (-99% to +1100%) and the occurrence of pairs or salvos. Although no patient received antiarrhythmic drugs, some patients showed a spontaneous change in arrhythmia which mimicked either drug suppression or drug-induced worsening of arrhythmias. If an antiarrhythmic drug had been given to these patients after the first half-hour, 65% would have been termed "drug responders," using the criteria of 50% reduction in ectopic beats and elimination of pairs or salvos during any half-hour period in the subsequent three hours. Spontaneous variability in ventricular ectopic beats causes serious problems when using ECG monitoring to evaluate antiarrhythmic drug response in individual patients. The arrhythmias averaged for the entire group remained stable during the recording period. Evaluating antiarrhythmic drugs by examining group response rather than individual patient response minimizes the effect of spontaneous variability.
The therapeutic value of lignocaine in acute myocardial infarction is still a subject of debate [1]. Some of the lack of success with this drug may arise from the use of inadequate dosage. Thus, several trials, such as those of Bennett
et al [2] and Chopra
et al [3], failed to show benefit, whereas relatively higher doses were used by Lie
et al [4] who did report success in preventing ventricular fibrillation. However, this was achieved at the expense of a 15% incidence of toxicity, underlining the fact that the therapeutic index of lignocaine is low.
In 417 consecutive cases of acute myocardial infarction (AMI) within a minimum of 21 days' stay in the Coronary Care Unit (CCU), primary cardiac arrest occurred in 41 patients (9.9%), the first episode occurring during ECG monitoring in 24 patients. After cessation of ECG monitoring, and within 2-25 days after admission, it occurred in 17 patients. Cardiac arrhythmias before the first cardiac arrest were analysed in these two groups of patients, and compared with the occurrence of cardiac arrhythmias within the first 5 days in 100 consecutive patients with AMI without complicating cardiac arrest. No significant difference in the frequency of cardiac arrhythmias could be demonstrated between the two groups with cardiac arrest and the control series. Moreover, complete absence of rhythm disturbances right up to the beginning of cardiac arrest was as frequent in the patient groups as in the control series (around 20%). As there is not sufficient evidence that treatment with antiarrhythmic drugs can provide safe prophylaxis against the occurrence of cardiac arrest, it is concluded that all patients with AMI should be kept in the CCU and monitored, by cable or by telemetry, for the duration of their stay. To achieve this, the cost in financial terms, manpower and reorganization is not a deterrent. Furthermore, this study does not give any support to the usual practice of confining possible attempts of prophylactic antiarrhythmic treatment to patients with arrhythmias of certain frequencies and/or types.
The efficacy of lidocaine to prevent ventricular fibrillation during the prehospital phase of suspected acute myocardial infarction was assessed 3 hours after administration in a randomized controlled trial. A total of 204 patients examined within 6 hours after onset of symptoms were included, and acute myocardial infarction was later confirmed in 63% of these. Lidocaine, administered as a 100 mg intravenous bolus dose followed by a 300 mg intramuscular injection, failed to prevent ventricular fibrillation, which was observed in 2 (2.1%) of 96 patients in the lidocaine group and in 3 (3.0%) of 101 patients in the placebo group (p = 0.95; odds ratio 0.7, 95% confidence interval 0.4 to 1.3). In addition, sudden cardiac collapse with unknown heart rhythm was observed in three patients who received lidocaine (3.1%) compared with none in the placebo group (p = 0.23; odds ratio 7.6, 95% confidence interval 2.8 to 22.1). The results of this small study suggest that lidocaine, even when given in a high dose, is ineffective in preventing ventricular fibrillation when administered before hospitalization for suspected acute myocardial infarction. Prophylactic use of lidocaine in this situation may therefore not be warranted or advisable.
The purposes of the present investigation were 1) to track the incidence of primary ventricular fibrillation (VF) in the control and lidocaine-treated groups in the randomized control trials (RCTs) of lidocaine prophylaxis against primary VF in acute myocardial infarction, with particular emphasis on the time frame of the randomized trial, and 2) to estimate the number of patients who must receive lidocaine currently to prevent one episode of VF.
The following variables from RCTs published between 1969 and 1988 were entered into logistic regression models to predict the percent of patients developing VF: year of publication of the RCT, method of data analysis used in the RCT, route and technique of lidocaine administration, duration of monitoring for VF, and exclusion criteria before randomization (congestive heart failure/cardiogenic shock, ventricular tachycardia/VF, or bradycardia/atrioventricular block). Year of publication was a significant predictor of VF in both the control and lidocaine groups (p less than or equal to 0.002) even after adjusting for other covariates. Based on a univariate logistic regression model with year as the predictor variable, it was estimated that the incidence of primary VF in the control group fell from 4.51% in 1970 to 0.35% in 1990 and from 4.32% down to 0.11% for the lidocaine group over the same time period. Thus, about 400 patients would currently need prophylaxis with lidocaine to prevent one episode of VF.
Present estimates of the risk:benefit ratio of lidocaine prophylaxis should consider the low risk of VF in control patients and the large number who need lidocaine prophylaxis to prevent one episode of VF. When added to the previously reported trend toward excess mortality in lidocaine-treated patients, these data argue against the routine prophylactic use of lidocaine in patients with acute myocardial infarction.
In acute myocardial infarction, lidocaine is considered the drug of choice for the treatment of malignant ventricular arrhythmias. While initially a so-called "selective" treatment strategy prevailed, in which lidocaine was administered only after the onset of certain "warning arrhythmias," the prophylactic use of lidocaine in acute myocardial infarction has been gaining wider usage in intravenous and intramuscular application in recent years. Both therapeutic applications have been found to be problematic of late, which has led to increasingly restrictive use of lidocaine. While in selective treatment forms, the definition and prompt recognition of the so-called warning arrhythmias created especially acute problems, the prophylactic therapeutic use is problematic due to the occurrence of sometimes serious side effects, which is to be expected as the size of the collective being treated increases. Both treatment forms also appear limited by the narrow preventive efficacy of lidocaine against malignant ventricular arrhythmias, especially against ventricular fibrillation. The current therapeutic recommendation for lidocaine in acute myocardial infarction should be limited to patients presenting with very frequent and complex ventricular arrhythmias, especially when these are elicited by an R-on-T phenomenon. Side effects and other therapeutic problems encountered when the therapeutic modality is switched or adjusted can be greatly reduced by careful dosing and selection of the optimal combination substances.
The suppression of ventricular fibrillation by antidysrhythmic drugs is well correlated with their ability to block potassium channels in nerve and cardiac membranes. Blockade of potassium channels reduces electrical inhomogeneities in action potential and conduction parameters that lead to ventricular fibrillation. These actions tend to effectively decrease the electrical size of the heart, which suggests a mechanism for antifibrillatory drug action. The receptor sites for antifibrillatory drug action (IK blockade) appear to be on the outside of the cardiac membrane whereas receptors for antiarrhythmic drug action (INa blockade) appear to be on the inside of the cardiac membrane.
The modulated receptor hypothesis states that sodium channels have a specific receptor for antiarrhythmic drugs. Therefore, two agents that block sodium channels by binding to this receptor are expected to compete for occupancy. Glycylxylidide (GX) is a deethylated metabolite of lidocaine that accumulates in patients on lidocaine therapy. In single, voltage-clamped cardiocytes, GX, like lidocaine, blocked cardiac sodium channels in a use-dependent manner. However, its kinetics of recovery from block were markedly different from lidocaine: at potentials between -80 and -100 mV, GX-blocked channels recovered faster and more completely than lidocaine-blocked channels but recovered more slowly at more negative potentials (-120 to -140 mV). If lidocaine and GX compete for a common receptor, then there are conditions in which addition of a "faster" drug to a "slower" drug will produce less block than the slower drug alone. At potentials between -120 and -140 mV, addition of GX (slower drug) to lidocaine always increased the level of block, but addition of lidocaine to GX decreased the block in four of nine experiments and did not increase it in three of nine experiments. Conversely, at potentials between -80 and -100 mV, addition of lidocaine (slower drug) to GX always increased block, whereas addition of GX to lidocaine reduced the level of block in five of 16 experiments and did not increase it in seven of 16 experiments. Thus, upon addition of more blocker, the sodium current increased in 36% of cases or did not decline in 76% of cases. These results can be explained by the modulated receptor hypothesis with two drugs competing for the same receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Lignocaine (lidocaine) and β-adrenoceptor antagonists are widely used after acute myocardial infarction. The therapeutic value of these agents depends on the achievement and maintenance of safe and effective plasma concentrations. Lignocaine pharmacokinetics after acute myocardial infarction (MI) are controlled by a number of variables. The single most important is left ventricular function, which affects both volume of distribution and plasma clearance. Other major factors include bodyweight, age, hepatic function, the presence of obesity, and concomitant drug therapy. Lignocaine is extensively bound to α1-acid glycoprotein, a plasma protein which is also an acute phase reactant. Increases in α1-acid glycoprotein concentration occur after an acute MI, decreasing the free fraction of lignocaine in the plasma and consequently decreasing total plasma lignocaine clearance without altering the clearance of non-protein-bound lignocaine. Complex changes in lignocaine disposition occur with long term infusions, and therefore early discontinuation of lignocaine infusions (within 24 hours) should be undertaken whenever possible. Because the risk of ventricular tachyarrhythmia declines rapidly after the onset of an acute MI, lignocaine therapy can be rationally discontinued within 24 hours in most patients.
Lignocaine has a narrow toxic/therapeutic index, so that pharmacokinetic factors are critical in dose selection. In contrast, β-adrenoceptor antagonists’ adverse effects are more related to the presence of predisposing conditions (such as asthma, heart failure, brady-arrhythmias, etc.) than to plasma concentration. The pharmacokinetics of β-adrenoceptor antagonists are important to help assure therapeutic efficacy, to provide information about the anticipated time course of drug action, and to predict the possible role of ancillary drug effects (such as direct membrane action) and loss of cardioselectivity. Lipid solubility is the main determinant of the pharmacokinetic properties of a β-adrenoceptor antagonist. Lipid-soluble agents like propranolol and metoprolol are well absorbed orally, and undergo rapid hepatic metabolism, with important presystemic clearance and a short plasma half-life. Water-soluble drugs like sotalol, atenolol, and nadolol are less well absorbed, and are eliminated more slowly by renal excretion. Clinical assessment of β-adrenoceptor antagonism is more valuable than plasma concentration determinations in evaluating the adequacy of the dose of a particular β-adrenoceptor antagonist.
This review considers the factors that determine the pharmacodynamic and pharmacokinetic properties of lignocaine and β-adrenoceptor antagonists after acute MI. These factors are then related to the principles of rational dose selection for these agents.
374 patients with suspected (and, later, confirmed) myocardial infarction were given intravenous lignocaine 60 mg. followed by lignocaine infusion at 0·5 mg. (group A) or 1 mg. (group B) per minute for forty-eight hours or no lignocaine (group C). There was no significant difference in the incidence of ventricular ectopic beats and tachyarrhythmias between the control and treated groups. Infusion of lignocaine at the dose levels used did not result in an increase in the incidence of cardiac failure, shock, or conduction disturbances.
The frequency of ventricular tachyarrhythmias has been compared in 114 control patients and in 108 patients receiving lignocaine by intravenous infusion at a rate of 2.5 mg. per minute for 48 hours. Significant arrhythmias were three times more frequent in the control group. The efficacy of lignocaine given prophylactically was demonstrated in patients with and without left ventricular failure or persistent hypotension. The frequency of ventricular tachyarrhythmias complicating both anterior and inferior infarction was reduced, but statistical significance was demonstrated only in patients with anterior infarction. Mortality was not significantly different in the treated and untreated patients, but lignocaine was administered to any control patient who had a ventricular tachyarrhythmia. The routine administration of lignocaine to all patients with suspected or proven myocardial infarction is recommended.
LIDOCAINE (Xylocaine) has become one of the most frequently used drugs in the treatment of ventricular arrhythmias, particularly those associated with acute myocardial infarction. It has been shown to terminate ventricular tachycardia, and it has been given to suppress multiple ventricular extrasystoles.1 , 2 The drug has been administered as an intravenous bolus or as a constant intravenous infusion. Although the use of lidocaine as an antiarrhythmic in postoperative cardiac surgery has been investigated,3 little objective information is available regarding the therapeutic and toxic doses in patients with myocardial infarction. Its effect on ventricular tachycardia can readily be shown, but the evaluation . . .
Thirty-five patients with ventricular dysrhythmias and seven with other dysrhythmias after acute myocardial infarction were treated with intravenous lignocaine.Satisfactory initial suppression of ventricular ectopic beats was achieved in 27 (82%) of 33 patients after either a 50-mg. bolus or a 50-mg. bolus followed by a 100-mg. bolus of intravenous 2% lignocaine. Continuous suppression of ventricular ectopic beats was accomplished in 21 (78%) of these 27 patients by continuous intravenous lignocaine infusions of 1 to 2 mg. per minute. Recurrence of ventricular ectopic beats occurred in four patients despite lignocaine infusion rates of up to 6 mg. per minute. Six patients with ventricular ectopic beats developed ventricular fibrillation despite satisfactory initial suppression of their dysrhythmia by lignocaine. In three of them ventricular fibrillation supervened while they were receiving a lignocaine infusion and two subsequently died. Unheralded ventricular fibrillation occurred in three other patients between four and seven days after completing the full course of lignocaine therapy.Toxic effects of lignocaine were minimal in patients receiving 1 to 2 mg. per minute.
A method has been described which permits the quantitation of infarct size following experimental coronary artery occlusion. The results were surprisingly uniform, despite the observed anatomic variation in potential collateral circulation. Ligations of the anterior descending branch of the left coronary artery (LAD) at a high site produced infarcts 20 percent or greater in 7 of 8 dogs. A midpoint occlusion (between 1.1 and 2.6 cm. from the origin of the LAD) yielded infarcts between 13 percent and 18 percent in 6 of 8 dogs. All 8 animals with low ligations (3.5 cm. or beyond) had infarcts between 2 percent and 7 percent of the ventricular muscle mass. Several serum enzyme measurements were made in an attempt to correlate infarct size with degree of elevation. The SGOT and LDH values were studied most extensively because they appeared to be most sensitive. The modified LDH which represents the heart isozyme can be measured readily. Elevation of this latter enzyme correlates more closely with infarct size than any other serum enzyme determination.
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