From Cuthbertson to Fast-Track Surgery: 70 Years of Progress in Reducing Stress in Surgical Patients

Abstract

Objective

To evaluate the evolution of knowledge concerning the stress response in surgical patients and to determine the therapeutic benefit of stress reduction therapy.

Summary Background Data

The stress response in surgical patients is associated with tissue catabolism, organ failure, and prolonged recovery. Understanding the neural-hormonal basis for these events has stimulated efforts to attenuate these undesirable effects. A review of the results of these efforts is important for the application of stress reduction therapy and further improvement of surgical care.

Methods

Medline was searched from 1980 to the present using the terms “stress response,” “neural-hormonal response,” “fast track surgery,” and “outcome in surgical patients.” These papers were reviewed along with historical information relating to early descriptions of metabolic and stress responses in surgical patients.

Results

Improved understanding of the stress response in surgical patients has occurred over the past 70 years. Multiple examples of stress reduction associated with decreased morbidity and mortality are reported.

Conclusions

Reduction of stress in surgical patients has improved outcome. The use of stress reduction techniques will continue to expand and contribute to the improvement of future surgical care.

Over the past 50 years surgical care has improved dramatically. Most observers related these changes to the seminal development of fields like cardiac, transplantation, vascular, and minimally invasive surgery. In addition, resuscitation of injured patients has greatly improved and systems of care delivery (such as ambulance services, emergency rooms, and specialty tertiary care facilities) have ensured that optimal treatment can be provided to critically ill patients. Finally, supportive measures used in intensive care units and operating rooms enhance outcomes. These areas include using physiologic monitoring, providing sophisticated anesthesia care and pain control, prescribing appropriate antibiotics, supporting patients by metabolic and nutritional means, and using new methods of imaging to aid in diagnosis.

All of these areas have added to the improved outcome in surgical patients. There is, however, one major advance that is reflected in all of these accomplishments: the reduction of stress in surgical patients. Stress reduction has contributed to improved operative outcomes, reduced complications, and greatly shortened length of convalescent recovery. This paper will review the remarkable advancements that have been made in this area over the past 70 years and discuss future trends.

WHAT IS STRESS?

Stress is a term applied to the fields of physiology ¹ and neuroendocrinology ² to refer to those forces or factors that cause disequilibrium to an organism and therefore threaten homeostasis. The stressors can be defined—whether they be physical injury, mechanical disruption, chemical changes, or emotional factors—and the body’s response to these factors can be carefully quantitated.

In mammals, complex sensory systems have evolved that result in reflex nervous system responses to the stressor and also alert the central nervous system (CNS) of the disturbance. Neurons of the paraventricular nucleus of the hypothalamus elaborate corticotropin-releasing hormone and activate the hypothalamic-pituitary-adrenal axis (HPA). Other areas of the brain stem signal the peripheral autonomic nervous system. These two systems elicit an integrated response, referred to collectively as the “stress response,” which primarily controls bodily functions such as arousal, cardiovascular tone, respiration, and intermediate metabolism. Activation of this system also influences many other functions of the CNS, such as feeding and sexual behavior, which are suppressed, and cognition and emotion, which are activated. In addition, this system alters normal gastrointestinal activity and depresses immune/inflammatory reactions.

The stress response in surgical patients is defined as the activation of this system: stimulation of the HPA is quantitated by the elevated secretion of glucocorticoids, and activity of the sympathetic nervous system is determined by quantitating catecholamine elaboration.

CUTHBERTSON AND THE INITIAL DESCRIPTION OF SYSTEMIC INJURY RESPONSES

As a young clinical chemist working in Glasgow, Scotland, in the late 1920s, David Patten Cuthbertson (Fig. 1) was assigned the project of studying calcium metabolism in patients following long bone fracture. The goal of the investigation was to determine if abnormal calcium balance was somehow related to fracture nonunion, a major clinical problem at the time. In his initial investigation, Cuthbertson studied normal volunteers and individuals with noninflammatory dysfunction of the knee joint; both groups were placed on complete bedrest and received no other active therapy. A fixed diet of known composition was provided daily and all urine and stool were collected and analyzed. Like any young, thorough clinical chemist, Cuthbertson analyzed the losses for multiple substances; not only were calcium and phosphorous measured, but so were nitrogen, potassium, sulfur, and creatine. He found that bedrest caused a slight increase in the excretion of most of these products, but with time whole body balance (intake-loss) gradually returned to baseline. ³

Figure 1. Sir David Cuthbertson (1900–1989), shown here with a commemorative plaque in his honor at the Glasgow Royal Infirmary, where he worked in the biochemistry department. Sir David was knighted in 1965 for his contributions to the field of animal and human nutrition.

The next study applied the same protocol to patients admitted to the hospital with fractures of the long bones of the lower extremities. To his surprise, calcium excretion changed little following injury, but there was a dramatic rise in the loss of nitrogen (as urea), potassium, phosphorus, sulfur, and creatine. These losses were much greater than those associated with bedrest along (as determined by his previous control data) and exceeded the quantity of intracellular constituents that would be accounted for by local tissue injury or even by the blood that was sequestered at the fracture site and subsequently reabsorbed. He concluded that the increased loss of intracellular constituents must represent a generalized reaction of the body associated with systemic breakdown of lean tissue, particularly skeletal muscle. ⁴

Subsequent studies verified the initial findings and established an association between fever and the posttraumatic catabolic state (e.g., posttraumatic fever). ⁵ Metabolic rate measurements documented a simultaneous rise in oxygen consumption that occurred at the peak of tissue catabolism. ⁵

Thus, the field of posttraumatic metabolism quantitating the effects of the stress response was born.

ASSOCIATION BETWEEN NEUROENDOCRINE RESPONSES AND THE SYSTEMIC METABOLIC RESPONSE

The early descriptive studies by Cuthbertson were soon replicated and extended by other investigators. ^6–9 An association between the system metabolic response and hormonal elaboration was soon sought, but this approach was initially hampered by methodological problems, for few sophisticated techniques existed to precisely measure actual stress hormones or their metabolites. However, early studies of combat casualties during World War II used a variety of indirect chemical and biologic measurement techniques and determined that there was increased elaboration of glucocorticoids following injury. These initial observations were confirmed by studies involving the actual measurement of blood corticoids, which were reported in the 1950s. ¹⁰

But what was the signal that initiated and propagated the immediate elaboration of these adrenal cortical hormones? In classic studies by Hume ¹¹ and Egdahl, ¹² the adrenal cortical response to limb injury in dogs was studied. In animals with an intact sciatic nerve or spinal cord, operative injury or superficial burn caused an immediate and sustained increase of adrenal hormones. If the nerve or cord were transected, the response was abated.

In additional studies, Hume demonstrated the importance of the hypothalamus, anterior median eminence, and anterior pituitary gland to this response. ¹¹ Thus, in this investigative setting, afferent nervous signals were essential to mediate the HPA stress response.

Hypothalamic activation of the autonomic nervous system results in increased secretion of catecholamines from the adrenal medulla and the presynaptic nerve terminals. While the physiologic effects of increased sympathetic nervous activity had been extensively described, ¹ it was exceedingly difficult to quantitate these hormonal responses. Work by von Euler et al. ¹³ and others helped to develop reliable assay techniques for catecholamines. Applying this methodology, Goodall et al. studied severely stressed thermally injured patients and found accelerated secretion rates of catecholamines associated with burn injury. ¹⁴ Others extended these investigations and related the activation of the sympathetic nervous system to other types of surgical trauma.

SATISFYING KOCH’S POSTULATES OF CAUSALITY

While associations had been made between stress hormones and systemic responses, little information was available to determine a direct cause-and-effect relationship. Thus, an approach was needed not unlike that proposed by Koch, who set forth a set of postulates that had to be satisfied before a microorganism could be said to be the cause of an infectious illness. ¹⁵ To prove causality, not only was an association between factors required, but the disease must resolve when the causative factor was eliminated. In addition, the disease had to be recreated when the agent was given to a normal organism.

In the case of catecholamines, a strong association was established between the hypermetabolic response of burn patients and the quantity of catechol secreted in the urine by investigators working at the U.S. Army Institute of Surgical Research. ¹⁶ This hypermetabolic response and secretion of catechols was sensitive to the changes in ambient temperature but was not dependent on the absolute environmental temperature. With wound healing and grafting, both catechol secretion and the hypermetabolic response abated. The hypermetabolic response could be greatly attenuated by administering β- but not α-adrenergic blocking drugs. Finally, the response could be created in normal individuals by infusing epinephrine.

Additional blocking studies in thermally injured children confirmed the impact of β-adrenergic blockade on cardiovascular and metabolic responses. ¹⁷

Evidence that supported a causal relationship between an injury and activation of the HPA axis was provided by Kehlet et al.: they used epidural anesthesia to block nervous afferent pathways to the CNS in individuals undergoing elective surgical procedures in the lower abdomen and on the lower extremities. ¹⁸ Such neuraxial blockade attenuated the activation of the HPA axis, dampened reflex neurogenic responses to the liver and intestinal tract, and greatly reduced pain. As a result, the stress-induced elaboration of catabolic hormones was inhibited, hyperglycemia was reduced, and the posttraumatic negative nitrogen balance was significantly attenuated.

Finally, Bessey et al. infused the stress hormones epinephrine, cortisol, and glucagon into normal volunteers over a 74-hour period to achieve blood levels observed in surgical patients. ¹⁹ The response was compared to a similar 4-day period of saline infusion. With the altered endocrine environment, there was significant hypermetabolism, negative nitrogen balance, glucose intolerance, insulin resistance, and leukocytosis, all responses characteristic of mild to moderate injury. Further endocrine manipulation, as observed with more severe stress, resulted in still greater body catabolism. ²⁰

Thus, through a series of blocking and infusion studies, causality between the stress response and stress hormones was established. Could this knowledge be applied to benefit surgical patients?

MODIFYING THE STRESS RESPONSE AND IMPROVING OUTCOME

Traditionalists have argued that it is better not to aggressively intervene in the care of critically ill patients but to allow systems that have evolved over thousands of years to provide the major homeostatic adjustment associated with illness. This approach may be appropriate in individuals with mild stress. However, intervention is the recommended therapy in the care of the critically ill by providing aggressive resuscitation, excising and closing wounds, draining pockets of infection, and providing pulmonary, metabolic, nutritional, and antibiotic support. These therapies have all proven to save lives and to be cost-effective. If further intervention were to modify systemic stress, it would be best to preserve the beneficial effects of the stress response (e.g., homeostatic adjustments, which resolve the stress and heal the wound) while attenuating the undesirable features of the response (e.g., catabolism, organ dysfunction, and organ failure).

The following examples demonstrate areas where it has been possible to modify the stress response and improve outcome.

Neuraxial Blockade Reduces Mortality and Morbidity

Epidural anesthesia and spinal anesthesia are known to modulate the stress response, and these techniques have been used for many decades. Data using surrogate endpoints have suggested benefits of neuraxial blockade over general anesthesia, but available clinical studies have not had sufficient power to conclude with certainty that this approach is superior to general anesthesia. A recent meta-analysis reviewed 141 trials including 9,559 patients and compared epidural or spinal anesthesia with general anesthesia. ²¹ Overall mortality was reduced about 30% in the patients allocated to neuraxial blockade when compared to general anesthesia. There was also a reduction in complications such as deep vein thrombosis, pulmonary embolism, blood loss, pneumonia, respiratory depression, myocardial infarction, and renal failure (Table 1). These changes were observed primarily in patients who underwent operations of the lower extremities or pelvis; additional studies are needed before these results can be extended with confidence to most general surgical procedures in the upper abdomen and thorax. Nonetheless, changes in mortality of this magnitude are rarely observed in contemporary medical care, even with the frequent introduction of so-called “blockbuster” drugs that are universally prescribed in clinical care.

Table 1. REDUCTION IN MORBIDITY WITH REGIONAL ANESTHETIC TECHNIQUES COMPARED WITH SYSTEMIC ANESTHESIA

From reference ²¹.

Preventing Hypothermia

During operations lasting more than 2 hours, patients are frequently subjected to cold stress, as operating rooms are cold and anesthetic agents interfere with the usual thermoregulatory defenses against cold exposure. Hypothermia results in stimulating the stress response, which increases elaboration of adrenal steroids and catecholamines when compared to euthermic patients undergoing similar procedures. ²²

When compared to normothermic controls, mild hypothermia (a fall of 1–3°C core temperature) results in a twofold to threefold increase in wound infections, an increase in blood loss, an increase in postoperative cardiac arrhythmias, including ventricular tachycardia, increased catabolism, and discomfort. ²³

Active prevention of hypothermia by heating the patient greatly reduces these risks, attenuating the stress of operation and improving outcome.

Adrenergic Blockade in Thermally Injured Patients

Although earlier studies suggested a relationship in burn patients between increased sympathetic activity and the catabolic response to burn injury, ^16,17 little clinical application of this information had been reported. Recently, Herndon et al. compared the results of long-term β-blockade with propranolol in thermally injured children with a comparable group of patients who served as controls. ²⁴ β-blockade decreased heart rate and oxygen consumption. Net muscle protein balance (synthesis-breakdown) was increased 82% over baseline in the treated group and decreased by 27% in the controls. Lean body mass was unchanged in the treated group but was reduced 9% in controls, documenting the catabolic effect of thermal injury despite aggressive nutritional support. The authors concluded that the treatment of children with burns with β-blockade attenuated the hypermetabolic response and reversed the protein catabolism associated with this major injury. Despite the investment of millions of dollars to develop anticytokine drugs that potentially could attenuate skeletal muscle catabolism, these investigators have found that a readily available inexpensive agent appears to be a safe and effective anticatabolic drug.

β-Blockade in Elective Surgical Patients With Heart Disease

Mangano et al. prospectively randomized 200 high-risk patients undergoing noncardiac surgery to receive β-blockade (atenolol) or placebo. ²⁵ Postoperative mortality was significantly lower among the treated patients compared to controls at 6 months (0 vs. 8%) and at 2 years (10 vs. 21%). In a subsequent investigation, Poldermans et al. studied high-risk patients undergoing noncardiac surgery. ²⁶ Fifty-nine received β-adrenergic blockade (bisoprolol) and 53 received placebo. Death from cardiac causes was 3.4% in the treated group and 17% in controls. The primary study endpoint of death from cardiac causes or nonfatal myocardial infarction occurred in 3.4% of the treated group and 34% in the standard care group (P < .001).

Activation of the sympathetic nervous system may result in myocardial ischemia and cause cardiac arrhythmias in susceptible patients due to coronary vasospasm, which decreases myocardial oxygen supply.

These data and the reports of others ²⁷ add support for the perioperative use of β-blockade in high-risk surgical patients.

Deep Opioid Anesthesia in Infants Undergoing Cardiac Surgery

Because extreme hormonal and metabolic responses to stress are associated with increased morbidity and mortality, Anand and Hickey explored the effects of attenuating the stress response in infants undergoing cardiac surgery by administering deep opioid anesthesia. ²⁸ In a randomized trial, 30 neonates received high-dose sufentanil with postoperative infusions of opiates for 24 hours. The control group received lighter anesthesia with halothane/morphine followed by postoperative injections of morphine and diazepam. The infants who received the deep anesthesia had significantly reduced responses of the stress hormones cortisol, catecholamines, and glucagon when compared to the control group. When clinical outcome was evaluated, the group receiving deep anesthesia had a decreased incidence of sepsis, metabolic acidosis, and disseminated intravascular coagulation and fewer postoperative deaths (0/30 given sufentanil vs. 4/15 given halothane and morphine, P < .01). In neonates undergoing cardiac surgery, the attenuation of the stress response was associated with reduced morbidity and mortality.

Fast-Track Surgery

“Fast-track surgery” is the combination of various techniques used in the care of patients undergoing elective operations. ²⁹ The methods used include epidural or regional anesthesia, minimally invasive operative techniques, optimal pain control, and aggressive postoperative rehabilitation, including early enteral nutrition and ambulation. This method of care has been shown to reduce the stress response ³⁰ and associated organ dysfunction; it optimizes recovery and prompts early hospital discharge (Table 2). ³¹ In general, only single-center studies are available to evaluate this approach, but future trends will incorporate these and other techniques into perioperative care and thus reduce the stress of operation even further. This approach should greatly reduce postoperative hospital stay and significantly shorten convalescent recovery.

Table 2. LENGTH OF STAY WITH FAST-TRACK SURGERY

From reference ³¹.

POTENTIAL PROBLEMS ASSOCIATED WITH STRESS REDUCTION

The stress response was programmed in higher organisms to provide homeostatic adjustments to factors such as cold exposure, volume loss, hypoglycemia, and inflammation. Using pharmacological means to attenuate or abolish these responses is not without risk, for it places responsibility on the care providers to minimize these and other potential external stressors and, if necessary, to respond therapeutically in an appropriate manner if an unexpected incident would occur.

This point was emphasized by Cannon 70 years ago. ¹ He devised a method to totally sympathectomize cats, and these animals could be maintained in a carefully controlled laboratory setting without difficulty. Yet they were unable to defend against hypoxia, fluid restriction, or the stress associated with changes in environmental temperature, hemorrhage, and severe exercise.

When using stress-modifying techniques, providers must be keenly aware of the potential problems associated with cold exposure, hemorrhage, and hypovolemia and sepsis in the treated patients. Protocols should be devised to treat these potential problems if they were to occur in patients undergoing stress reduction therapy.

Moreover, protocols should be extended to evaluate some of these approaches in a broader range of surgical patients. For example, spinal and epidural blocking techniques need to be evaluated in patients undergoing operations in the upper abdomen and thorax, and blood loss between treatment and control groups needs to be carefully evaluated. There is growing enthusiasm for the use of β-blockade in all types of surgical patients, yet the studies to date have been restricted to specific high-risk groups. ²⁷ Additional studies are needed to provide evidence that such an approach is safe and beneficial if applied in a more liberal manner.

FUTURE STUDIES

Additional clinical investigations need to be directed toward stress reduction in various groups of surgical patients. In patients undergoing elective operations, one new approach might be to provide β-blockade and adequate morphine analgesia to patients undergoing general surgical procedures in the upper abdomen. The deleterious effects on the bowel of administering opioids could be reversed by providing a selective morphine antagonist that attenuates the postoperative ileus associated with opioid use. ³²

In experimental animals, systemic inflammatory responses can be blocked by injecting very small quantities of cytokine antagonist or nonsteroidal inflammatory agents into the CNS, thus blocking the central reflex arc that propagates the stress response. ³³ Designer drugs that affect specific areas of the CNS and allow modification of the central stress response associated with severe inflammation could be developed and possibly could attenuate the deleterious effects of sepsis and the sepsis syndrome. Alternatively, intrathecal steroids, which have been used for other conditions, or nonsteroidal antiinflammatory agents administered via the spinal canal might also effectively attenuate the stress response in conditions associated with extensive inflammation, and this approach could be evaluated in a carefully controlled, experimental setting.

Cuthbertson’s observations that severe injury initiated systemic catabolic responses were later extended, and a causal association was made between the catabolic response and increased elaboration of the stress hormones catecholamines and glucocorticoids. A variety of approaches have been used to attenuate the stress response and improve outcome. Reducing the stress associated with surgical illness has decreased morbidity and mortality and contributed significantly to the improved outcome in surgical patients. Further advances in this approach will continue to enhance surgical care in the future.