Darwinian medicine: Does intensive care kill or cure?

19 August 2010 by Dan Jones 

We've evolved ways to come back from the brink of death – and doctors' efforts to help may just be getting in the way

NOTHING epitomises cutting-edge medicine so much as a modern intensive care unit. Among the serried ranks of shiny chrome and plastic surrounding each bed are machines to ventilate the lungs and keep failing kidneys functioning, devices to deliver drugs intravenously and supply sedatives, tubes to get food into a patient and waste out, and countless gizmos to monitor blood composition, heart rate, pulse and other physiological indicators.

This environment is home to Mervyn Singer, director of the Bloomsbury Institute Centre for Intensive Care Medicine at University College London. So you might expect him to wax lyrical about the wonders of medical technology. Instead, he has this to say: "Virtually all the advances in intensive care in the past 10 years have involved doing less to the patient." And he goes further, arguing provocatively that modern critical care interferes with the body's natural protective mechanisms- that patients often survive in spite of medical interventions rather than because of them.

It is a counter-intuitive idea, to say the least, yet there is an underlying logic. Taking an evolutionary perspective, Singer points out that the human body is adapted to deal with the types of threats to which our ancestors were exposed and those include critical illness. Our immune system can fight off infections, our blood clots so that we don't bleed to death with every cut, tissues regenerate and bone fractures heal, if imperfectly, over time. "We have evolved to deal with temperature extremes, starvation, trauma and infection," says Singer. "We haven't evolved to cope with being sedated, put on a ventilator and pumped full of drugs."

The human body is adapted to deal with the types of threats to which our ancestors were exposed

Such Darwinian thinking about health and illness is not new. It has been popular in certain quarters for more than a decade but it is still not a part of mainstream medicine and is especially rare in intensive care. "The application of evolutionary thinking in critical care medicine has been surprisingly lacking," says Randolph Nesse, a pioneer of Darwinian medicine at the University of Michigan, Ann Arbor. "Much of critical care medicine is based on a tacit theory that is rarely examined- namely, that almost all of the changes seen in severe illness are pathological." With his evolutionary approach, Singer holds this assumption up to scrutiny, and asks whether the changes are actually coping strategies, meaning that modern medicine might be interfering with the body's natural protective mechanisms.

Patients can end up in an intensive care unit for many reasons: they may have survived an accident, succumbed to a serious infection or undergone major surgery. Yet, once there, their condition often follows a similar clinical path because the body responds to trauma and infection in similar ways. Both elicit a strong local inflammatory immune response at the site of injury or infection. This helps fend off microorganisms that might enter the body, and also rallies immune cells to break down damaged tissue. While these responses cause local tissue damage prior to healing, they protect the body as a whole.

In severe cases, however, a localised reaction can become a body-wide systemic inflammatory response syndrome (SIRS). If infection is the trigger, this response is called sepsis. In the first "acute" stage of sepsis or SIRS, the immune system ramps up its activity, stress hormones are released and metabolism increases. Patients typically experience abnormal body temperature, a high heart rate and increased breathing. In the best-case scenario, they return to normal, but in many patients severe inflammation progresses over a period of hours or days and begins to affect the normal functioning of the body's organs. If equilibrium cannot be restored, multiple organ failure can set in.

This is the leading cause of death for critically ill patients in ICUs, accounting for more than two-thirds of deaths after the first week. The initial trauma often involves blood loss, severe vomiting, diarrhoea and excess sweating. Later, the overblown inflammatory response can cause fluid to leak out of the circulation and into the tissues. This fluid loss means less oxygen reaches organs, causing cells to die. That, at least, is the accepted view. Singer is not convinced.

He points to evidence from post-mortem studies on patients who have died after multiple organ failure, whose organs in fact look normal, with little sign of damage from a lack of oxygen (Critical Care Medicine, vol 27, p 1230). In addition, where patients survive multiple organ failure, normal function is rapidly restored, even in organs with little capacity for regeneration (Anaesthesia, vol 56, p 124). After acute renal failure, for example, only 1 per cent of sufferers need lifelong dialysis. There is also evidence that during the "multiple organ dysfunction" phase of sepsis and SIRS, oxygen still reaches the organs- they just use less of it for metabolism (Critical Care Medicine, vol 22, p 640).

 In light of these findings, Singer concludes that organs do not fail so much as shut down in an adaptive response to the extreme physiological stress of critical illness. His interpretation of the process goes as follows: during the first hours and days after major trauma or infection, the body enters an inflammatory "fight mode", burning energy and pumping out stress hormones such as adrenaline and cortisol, as well as chemicals that modulate the immune response such as cytokines and the gas nitric oxide. If this doesn't work, metabolism starts to drop, triggered by a decrease in energy production by the mitochondria, the cell's powerhouses. This happens because the hormones and immune chemicals produced during severe, prolonged inflammation inhibit and damage mitochondria, and changes in gene expression limit the production of new ones. Under these conditions, attempts to maintain normal functioning can trigger cell death. To avoid this fate, cells switch to a dormant metabolic state, causing organs to shut down.

In Singer's view, multiple organ dysfunction is a strategic and temporary functional change, comparable to hibernation or torpor. Far from being a catastrophic development that must be mitigated at all costs, it is the body's ultimate attempt to save its organs. By slowing metabolism right down, organs have a better chance of resuming their normal function, if and when the critical illness passes. It's a risky strategy, but then desperate times call for desperate measures.

Singer's thesis isn't just a novel way of interpreting multiple organ failure, it could also explain one of the big mysteries of intensive care- why many drugs and interventions have been linked to a worse outcome for critically ill patients. For example, certain types of antibiotics and sedatives damp down energy production by mitochondria (PLoS Biology, vol 2, p e167), so if given early they might interfere with the high-energy requirements of the acute phase of critical illness. What's more, antibiotics and sedatives interfere with immune functioning and can also cause problems for patients who survive organ shutdown and need to re-establish normal metabolism. This is because the drugs keep energy production low and also prevent the formation of new mitochondria to replace those lost during organ shutdown.

Singer recently published the definitive statement of his hypothesis (Current Opinion in Critical Care, vol 15, p 431). And earlier this year, he presented the idea at the conference Evolutionary Approaches to Disease and Health, held at Brunel University, London, where it generated considerable interest among an audience of evolutionary-minded researchers. Nesse, who was at the meeting, is enthusiastic. "Singer's work is a fine example of the value of evolutionary thinking in medicine," he says. He has long campaigned for trainee doctors to be taught evolutionary biology as a foundation for understanding what the human body is and how it works.

Intensive care specialists are also open to Singer's views, if only to invigorate the discipline. "It's time for some new ideas," says Falco Hietbrink, at the University Medical Center in Utrecht, the Netherlands. "Although we've tried hard over the past 40 years to improve patient outcomes, mortality rates have dropped only slightly." Nevertheless, some clinicians will require more convincing. "I love imaginative hypotheses, and this is a fascinating possibility," says Luciano Gattinoni of the Institute of Anaesthesia and Intensive Care at Ospedale Maggiore Policlinico in Milan, Italy. However, he points out that there is scant autopsy evidence on whether multiple organ dysfunction causes cell death or serves a protective role. "Really, we don't have enough data to settle these questions, which is quite surprising."

Last-ditch response

Another obvious criticism of the idea that multiple organ dysfunction is adaptive is that it is not tremendously successful as a survival strategy. Not only is organ failure a principal cause of death among people in intensive care, the more organs that fail, the more likely a patient is to die. And among patients who survive, the severity of multiple organ failure correlates with quality of life in the long term.

Singer acknowledges that, at best, it is only a partially successful strategy- though one that may allow the hardy to survive to fight another day, an obvious evolutionary advantage. In fact, he is impressed by how effective it is, given that it is a last-ditch response. Witness the high survival rates among injured soldiers in the days before sophisticated medical interventions (see "Battle hardened"). For Singer's money this points to a remarkable capacity for coping with extreme trauma.

The key issue, of course, is what all this means for treatment. "If some aspects of the condition are adaptive, then clinicians should work with them, not against them," says Singer. For starters, doctors might want to reconsider the doses and course durations of antibiotics and sedatives. Likewise for interventions designed to enhance oxygen delivery to tissues. These may prove beneficial when given early, but could be ineffective or even harmful later on if the extra oxygen bumps up metabolic activity that cannot be supported by the mitochondria and so leads to cell death. In addition, critically ill people might benefit from the timely administration of therapies that protect mitochondrial function, such as antioxidants. Likewise treatments that stimulate the production of new mitochondria, including hormones like oestrogen and the gas nitric oxide. The precise therapeutic implications of re-thinking organ dysfunction will depend on acquiring clinical evidence about what works and what does not. "Evolutionary medicine does not prescribe what treatment is best," says Nesse. "[It] suggests what we should think about and what studies we should do." But if the upshot is that intensive care becomes less intensive that might not actually be so revolutionary - there is already a trend to reduce levels of intervention in critical care (see "Less is more").

Singer may not be correct in every detail, but in the long run being provocative could be more important than being right. "Singer will get people thinking in new ways and doing new studies," says Nesse. In terms of improving the care of critically ill patients, that's got to be what the doctor ordered.

Battle hardened

Records from historical battles provide evidence for the remarkable capacity of the human body to cope with massive trauma. The Battle of Trafalgar, which took place on 21 October 1805, was a particularly bloody affair: by the end of the day there were more than 450 British fatalities, while the Spanish and French forces suffered the loss of more than 3200 soldiers. Thousands more were wounded. William Beatty, the physician on the British flagship HMS Victory recorded 102 wounded soldiers on board. Despite having none of the medical technology available to today's intensive care patients and performing 10 amputations, only six of the wounded subsequently died of their injuries.

Ten years later, a similarly high survival rate was recorded among the 13th Light Dragoons in the Battle of Waterloo. Only three of the 52 wounded soldiers later died of their wounds.

Medical records from the American Civil War between 1861 and 1865 tell the same story. Approximately 15 per cent of all mortalities occurred on the battlefield, with around twice as many soldiers dying from diseases as a result of poor sanitation and living conditions.

Amputation was the main treatment for injuries, with surgeons working around the clock to remove limbs and digits. Operations often took no more than 10 minutes and, with little water available, hands and instruments went unwashed between procedures. Despite all this around three-quarters of amputees survived.

Less is more

Intensive care medicine is only about 50 years old. In the early days the logic of treatment seemed commonsensical. "We thought, 'antibiotics are good, so more antibiotics are better. Breathing is good, so more air is better'," says Luciano Gattinoni at Ospedale Maggiore Policlinico in Milan, Italy. "We were doing the right things conceptually, but exaggerating everything." Nowadays, the trend is for less intervention, not more.

Perhaps the biggest advance in the past decade has been in the way patients are mechanically ventilated. Pumping air into the lungs can damage them, because they are normally inflated by inhalation, in which negative pressure draws in air. By reducing the volume of air pumped in each breath cycle and increasing the frequency of artificial breaths, mechanical ventilation has become much more successful.

Doctors also recognise that even essential interventions can cause problems. Entry points for tubes can become infected, which can prove fatal for patients in a weakened state. Sedatives have been linked to poor patient outcomes in some studies (The Lancet, vol 371, p 126). Working on the assumption that intensive care should support patients while not adding to the stress that their bodies are under, the idea that less is more is increasingly mainstream.

Dan Jones is a science writer based in Brighton, UK