Acute nociceptive pain is a signal of tissue injury and perception is initially adaptive, causing an organism to take steps to decrease the tissue damage. In other words, the ability to sense pain is basically a protective mechanism. Surgery, however, creates an acute pain that is different from the pain of stepping on a nail, because the noxious stimulus is sustained by the sheer volume and severity of the tissue disruption. In general, the response is proportionate to the magnitude of the tissue trauma, although there is a huge degree of variability between individuals.¹ In the periphery, the injury causes erythemia, vasodilation and activation of nociceptive receptors. The nociceptive signals are transmitted within peripheral nerves to the spinal cord and rostal. Sustained nociceptive stimuli alter the process to increase nociceptive transmission and hence, the perception of pain. In the periphery this is caused by tissue mediators released by cellular damage causing edema, vasodilation and capillary permeability all of which increase peripheral nociceptive signals within the wound to a maximum (peripheral hypersensitivity). An analogous phenomenon occurs in the dorsal column of the spinal cord. Sustained peripheral nociceptive signals cause accumulation of neurotransmitters in the dorsal column, which lowers the threshold for nociception of the receptors and increases the size of the receptor fields. This has the effect of creating maximum nociceptive transmission (central hypersensitivity).
Direct Cardiovascular Effects
The first cardiovascular consequence of ascending nociception is recruitment of segmental spinal reflexes from interneuronal connections. These spinal reflexes create increased sympathetic activity which increases heart rate, stroke volume and peripheral resistance.²Increased sympathetic tone also causes visceral vasoconstriction, increased sphincter tone and uncontrolled skeletal muscle activity.² All of these increase myocardial work and oxygen demand. The response is proportional to the magnitude and duration of the stimulus. The increase in heart rate decreases diastolic filling of the coronary arteries, having the further deleterious effect of decreasing myocardial oxygen delivery during a time when demand is increased. In patients with coronary artery disease, cardiomyopathy or ventricular hypertrophy secondary to aortic stenosis, this supply/demand imbalance can trigger myocardial ischemia.
Increased sympathetic tone can have direct deleterious effect within the heart. Alpha receptors within coronary arteries respond to sympathetic stimulation at a variable threshold level with vasoconstriction.² The resultant coronary artery spasm can induce angina, myocardial ischemia and even infarction. Coronary vasoconstriction may be even more likely in abnormal coronary arteries.³⁻⁴ Analgesia may also be more important in the same patients.⁵ Hypercoagulability has been implicated in the genesis of angina and myocardial ischemia after major surgery.6 Analgesia has been associated with reduction of this hypercoagulability, presumably by prevention of activation of platelets or improved fibrinolysis.⁶˒⁷
Peripheral Cardiovascular Effects
There are also deleterious peripheral cardiovascular effects in response to acute pain. Sustained acute pain reduces peripheral blood flow. Decreased venous flow causes stasis and ideal conditions for clotting. Venous thrombosis increases significantly.²Increased venous thrombosis increases thromboembolic complications. Reduced blood flow increases acute thrombosis in peripheral vascular grafts.⁶Reduced renal and hepatic blood flow is observed but not associated with organ injury unless pre-existing chronic organ failure exists. Acute pain may impair fibrinolysis⁷ which further increases the increased risk for proximal lower extremity thromboembolism, known to be highly associated with pulmonary embolism and morbidity.
Neuroendocrine System Effects
Even more indirect evidence of the effect of severe pain on the cardiovascular system comes from the response of the neuroendocrine system to severe acute pain. The response is multi-factorial but includes cellular, immunological and neuroendocrine consequences. The primary systems that respond to stress are the hypothalamic-pituitary-adrenal axis and activation of the sympathetic nervous system by the adrenal glands. Both result in catecholamine secretion, catabolic hormone secretion, and increased oxygen demand.⁸ Free fatty acids are increased during stress and also increase myocardial oxygen consumption.⁹Thoracic epidural analgesia attenuates pain and reduces the catecholamine surge associated with acute pain.¹⁰ Increased sympathetic tone decreases epicardial blood flow by increasing resistance from alpha-receptor stimulation.¹¹ Normal subjects compensate by metabolic messengers, but this can be impaired in patients with coronary artery disease. Paradoxic vasoconstriction can occur in diseased coronaries due to sympathetic stimulation that would produce vasodilation in normal coronaries.¹²⁻¹³ Severe pain activates the stress response2 which increases perioperative cardiac morbidity. Excellent analgesia, however, severely reduces this risk.¹⁴
Observations
The connection between acute pain and cardiovascular changes is supported observationally. The evidence is indirect but convincing. In humans, epidural analgesia prevents perception of noxious stimulus, reduces nociceptive transmission and prevents/reverses the cardiovascular changes.²˒¹⁵Animal evidence connects noxious stimulus with coronary vasoconstriction using methodology not ethically possible in humans. Prevention of noxious stimulus with epidural block increases myocardial oxygen concentration in animals¹⁶ and may reduce myocardial ischemia.¹⁷
Some of this indirect evidence is confirmed by human studies. Weak evidence suggests less episodes of perioperative myocardial ischemia when nociceptive transmission is reduced by preoperative epidural blockade¹⁴˒¹⁸ or subarachnoid block.¹⁹ An overall decrease in cardiovascular complications in patients who received regional anesthesia compared to general anesthesia were observed by Yeager²⁰ although the power of these observations were reduced by randomization issues.
...excellent analgesia could be established and sustained with intravenous administration of lower doses of opiates at shorter intervals.
History of Perioperative Pain Treatment
The philosophy for treatment of acute pain has undergone a major change over the last two decades. Traditionally, acute pain was the responsibility of the surgeon but a representative sample of these surgeons did not think that acute pain was pathological,²¹ believing, instead, that pain motivated their patients to recover and that analgesia delayed recovery. The treatment of acute pain was based on reaction to clinical experiences with on-demand parenteral analgesia for severe pain. The conservative approach was to order intramuscular (IM) opiates (morphine, meperidine) on a PRN basis with a four-hour dose interval and observation of the result influencing the dose selection. Typically, the patient would experience pain and request analgesia. The nurses would be forced to wait the four hour interval or call the surgeon. There would be the further delay of finding the drug keys, verifying and drawing up the medication and the latency from IM injection to analgesia. With all the delay from perception of pain to analgesia, pain would accelerate from moderate to severe or excruciating. The combination of observing this severe pain and the repeated calls for rescue²² analgesia led the surgeons to alter their dosing pattern. A few would shorten the dose interval but most would not for fear of complication. Opiate-induced respiratory depression was a serious complication and management was unfamiliar. Severe pain on the other hand was considered adaptive. Most altered their pain orders by increasing the dose of opiate per injection without shortening the interval and by adding a sedative. The larger dose, compounded with an anxiolytic, would produce a somnolent patient. Inevitably, the cycle would begin again with sedation yielding to pain, evolving to severe pain prior to the next analgesic intervention. The roller coaster ride was so variable that the idea of observing steady-state effects of either severe pain or excellent analgesia was clearly impossible.
Analgesia Paradigm Shift
The change in paradigm came from the observation that excellent analgesia could be established and sustained with intravenous administration of lower doses of opiates at shorter intervals. Extending excellent operating room analgesia was first observed with pain control in the post-anesthesia care unit (PACU). Extension of this approach made sustained excellent analgesia possible in surgical intensive care units using liberal dosing intervals. This logically gave way to continuous infusion of analgesics. Sustained analgesia became possible and the obvious improvement in well-being was coupled with the observation that side-effects were reduced and less total opiate was needed in many cases. This created the idea of an approach to provide sustained analgesia to even those patients not in a critical care bed. One such application is patient controlled analgesia (PCA) which uses pumps to deliver planned doses at safe intervals based on the need of the patient. At first perception of pain, the patient activates the pump and immediately receives a treatment. The analgesia is delivered before pain can accelerate and the anxiety that develops while waiting for analgesia is eliminated. Programming determines the size of each dose and the number of doses possible per unit time, to ensure safety. Pain scores, anxiety, and levels of sedation remain stable and satisfaction with analgesia increases. This change created the opportunity to study the outcome of sustained excellent analgesia. Other skills natural to anesthesiology came to be increasingly applied to acute pain with the same objective: stable, sustained analgesia. They have included intrathecal opiates, neuraxial and peripheral nerve catheters, or single-shot techniques with long-acting local anesthetics.
Conclusion
Direct effects include increased heart rate, stroke volume and peripheral resistance, which increase myocardial oxygen demand. The increased heart rate decreases diastolic filling time, which can decrease coronary blood flow and oxygen delivery. Indirect effects of severe acute pain cause activation of the stress response. Sympathetic activation and catecholamine release can cause epicardial vasoconstriction and reduced coronary artery diameter, further increasing the risk of myocardial ischemia. Other indirect effects cause increased coagulability, which increase the incidence of thromboembolism and increase the risk of acute thrombosis of vascular grafts. Most evidence suggests that excellent analgesia attenuates or eliminates these risks. Outcome studies support this observation and suggest that excellent analgesia should be an essential element in the prevention of perioperative cardiac complications and required for perioperative care of patients with known cardiac disease.