Targeting for cardioplegia: arresting agents and their safety.

Elective temporary cardiac arrest (cardioplegia) is often required during cardiac surgery. In the 1970 s, the development of hyperkalaemic cardioplegic solutions revolutionised cardiac surgery by offering effective chemically-induced cardiac arrest and myocardial protection during global ischaemia. Despite remaining the most widely-used cardioplegic technique, hyperkalaemia can have detrimental effects due to the Na and Ca loading of the cardiac cell induced by depolarisation of the cell membrane. Efforts over the last two decades to establish better cardioplegic agents have mainly remained limited to animal experiments. The failure of these approaches to progress to clinical trials may be due to a lack of clear criteria that a cardioplegic agent should meet at a cellular level and, more importantly, at a system level. In this review we attempt to define the criteria for the optimal cardioplegic agent. We also assess the suitability and clinical potential of previously-studied cardioplegic agents and suggest cellular targets, particularly those involved in cardiac excitation-contraction coupling, that may prove to be attractive options for the development of new cardioplegic drugs. Finally, we propose a multicellular target approach using a combination of pharmacological agents in order to offer better cardioplegic solutions.

Cardioplegia and cardiac surgery: pharmacological arrest and cardioprotection during global ischemia and reperfusion.

Since the start of cardiac surgery in the 1950s, multiple techniques have been used to protect the heart during the surgical requirement for elective global ischemia (and the still, relaxed, bloodless field that this provides the surgeon for repair of the lesion). Most of these techniques have been discarded. The current gold standard, established over 30 years ago, is hyperkalemic (moderately increased extracellular potassium) cardioplegia; this technique revolutionized cardiac surgery, allowing significant surgical advancement with relative safety. Hyperkalemic cardioplegia induces a rapid depolarized arrest that is readily reversible. Recent patient demographic changes, with surgeons operating on older, sicker patients who have more severe and diffuse disease, potentially requires a more prolonged elective ischemia; hence, an improved myocardial protection would be of benefit. Several areas of study have demonstrated that a new concept of myocardial protection--'polarized' arrest--may provide this additional protection. Many pharmacological agents have been shown (in experimental studies), to have the ability to induce a polarized arrest and to provide improved protection. However, the often-overlooked requirements of effect reversibility and systemic safety have meant that these agents usually remain experimental in nature. This review attempts to highlight the cellular components that can be targeted, within the excitation-contraction coupling cascade, to induce cardiac arrest, and to provide an explanation for the mechanism of action of these agents. In this context, the agents are discussed in terms of their clinical potential for use during cardiac surgery, with particular reference to the safety aspects of the agents.

Esmolol cardioplegia: the cellular mechanism of diastolic arrest.

AIMS: Esmolol, an ultra-short-acting beta-blocker, acts as a cardioplegic agent at millimolar concentrations. We investigated the mechanism by which esmolol induces diastolic ventricular arrest. METHODS AND RESULTS: In unpaced Langendorff-perfused rat hearts, esmolol (0.03-3 mmol/L) had a profound negative inotropic effect resulting in diastolic arrest at 1 mmol/L and above. This inhibition of contraction was maintained during ventricular pacing. At 3 mmol/L, esmolol also abolished action potential conduction. To determine the cellular mechanism for the negative inotropism, we measured contraction (sarcomere shortening) and the calcium transient (fura-2 fluorescence ratio; Ca(tr)) in electrically-stimulated rat ventricular myocytes at 23 and 34 degrees C. The decrease in contraction (by 72% at 23 degrees C, from 0.16 +/- 0.01 to 0.04 +/- 0.01 microm, P < 0.001) was similar to that of isolated hearts and was caused by a large decrease in Ca(tr) (from 0.13 +/- 0.02 to 0.07 +/- 0.02, P < 0.001). There was no additional effect on myofilament Ca(2+) sensitivity. Esmolol's effects on contraction and Ca(tr) were not shared or altered by the beta-blocker, atenolol (1 mmol/L). Sarcoplasmic reticulum inhibition with thapsigargin did not alter the inhibitory effects of esmolol. Whole-cell voltage-clamp experiments revealed that esmolol inhibited the L-type calcium current (I(Ca,L)) and the fast sodium current (I(Na)), with IC(50) values of 0.45 +/- 0.05 and 0.17 +/- 0.025 mmol/L, respectively. CONCLUSION: Esmolol at millimolar concentrations causes diastolic ventricular arrest by two mechanisms: at 1 mmol/L (and below), the pronounced negative inotropic effect is due largely to inhibition of L-type Ca(2+) channels; additionally, higher concentrations prevent action potential conduction, probably due to the inhibition of fast Na(+) channels.

Does intermittent cross-clamp fibrillation provide equivalent myocardial protection compared to cardioplegia in patients undergoing bypass graft revascularisation?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: does intermittent cross-clamp fibrillation provide equivalent myocardial protection compared to cardioplegia in patients undergoing bypass graft revascularisation? Altogether, 58 papers were found using the reported search, of which 13 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We identified 13 studies, of which eight were randomised prospective trials. None of these studies found increased mortality, seven analyzed serum cardiac enzymes and showed that intermittent ischemic arrest provides equal or better protection compared to cardioplegic techniques. Two studies found an increased usage of inotropes and intra aortic balloon pump (IABP) in the intermittent ischemic arrest group. We conclude that intermittent cross-clamp fibrillation is a versatile and cost-effective method of myocardial protection, with the immediate postoperative outcome comparable to cardioplegic arrest in first-time coronary artery bypass graft (CABG). The ischaemic duration associated with intermittent cross-clamp fibrillation is invariably shorter than that associated with cardioplegic arrest, and this may be one explanation for the comparable outcomes. There may also be an element of preconditioning protection during the intermittent cross-clamp fibrillation method, as has been shown experimentally. During elective CABG in patients with no clinical evidence of aortic or cerebro-vascular disease, the incidence of peri-operative microemboli (ME) and postoperative neuropsychological disturbances are shown to be comparable with both techniques of myocardial preservation.

In patients with acute aortic intramural haematoma is open surgical repair superior to conservative management?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: in patients with acute aortic intramural haematoma (IMH) is open surgical repair superior to conservative management. IMH is defined as a clinical condition related to but pathologically distinct from aortic dissection. In this potentially lethal entity, there is haemorrhage into the aortic media in the absence of an intimal tear. Altogether more than 204 papers were found using the reported search terms, from which six systematic reviews represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. IMH represents 17% of all dissections, whereas in postmortem studies this condition is found in 4-13%. The 30-day mortality of IMH is 24% (36% with type A and 12% with type B IMH; P<0.05). With surgical repair, 30-day mortality of type A IMH was 14% for patients treated surgically and 36% for patients treated medically with a P-value of 0.02. Survival at 1, 2, 3, 5 and 10 years was respectively: 81+/-21%, 87+/-8%, 83+/-6%, 65+/-22% and 44+/-14%. In contrast, with 8% mortality associated with medical treatment, prognosis of type B IMH is more favourable without surgical intervention, the latter associated with a 30-day mortality of 33% (P<0.05). Symptomatic patients and those with rapid progression or overt dissection during follow-up need emergent surgery. Ascending aortic diameter of >50 mm or subadventitial haematoma thickness of >12 mm should be considered as the candidates for early surgery. Although IMH seems to have an improved prognosis over aortic dissection, survivors of IMH are at significant risk for progressive aortic abnormalities, including aortic rupture, aneurysm, and ulceration. We conclude that surgical treatment of aortic IMH involving the ascending aorta with open distal replacement of ascending aorta results in lower mortality and longer survival compared to conservative management. IMH affecting the descending aorta can be managed with medical or endovascular interventional approach. In this latter group, serial imaging of the aorta is recommended, as aneurysm formation is not uncommon.

Large subpectoral hematoma: possible complication of sternotomy post-cardiac surgery.

A 62-year-old female patient developed a significantly enlarged left breast 6 hours after sternotomy for a coronary artery bypass graft operation. This was the result of subpectoral bleeding caused by a sternal wire.

Is blood versus crystalloid cardioplegia relevant? Significantly improved protection may require new cardioplegic concepts!

The predominant method of myocardial protection during cardiac surgery is hyperkalaemic cardioplegia, inducing depolarised arrest. Since its development in the 1970s, the only real change has been to alter the vehicle to blood. Although blood cardioplegia was shown to be 'superior' to crystalloid cardioplegia, this advantage is marginal and might explain the continuous use of crystalloid cardioplegia by some surgeons. To achieve significant improvements in cardioplegic protection, more radical and conceptual changes in the solution, such as those potentially achieved by 'polarised' arrest, should be explored.