Key Point:

Vasopressin may be useful for improving outcomes in sepsis patients, but until the results of more randomized controlled trials are available, physicians should exercise caution in administering the agent.

ORLANDO, FLA—Can the antidiuretic hormone vasopressin safely and effectively improve outcome in sepsis patients with vasodilatory shock? This question was debated at this year’s annual meeting of the Society of Critical Care Medicine.¹ Donald Landry, MD, PhD, argued that because septic shock is a state of vasopressin deficiency, administration of the hormone at a low dose to selected patients should increase their chances of survival. James Russell, MD, countered that until the results of more randomized controlled trials are available, vasopressin should not be routinely administered to sepsis patients.

VASOPRESSIN MAY BE USEFUL

According to Dr. Landry, a Professor of Medicine and Director of the Division of Experimental Therapeutics at Columbia University College of Physicians and Surgeons in New York City, a low-dose infusion of exogenous vasopressin induces a brisk pressor response in sepsis patients but shows little effect in normal subjects. “Brisk response to low-dose infusion would be observed in those situations where the sensitivity mechanism is activated and vasopressin receptors are not occupied by the endogenous hormone,” he asserted. In fact, endogenous levels of the hormone were low. “Our finding of low endogenous levels and the brisk response to exogenous hormone suggested that we had discovered a new hormone deficiency syndrome,” he argued.

“Vasopressin antagonizes the vasodilatory mechanisms that are activated during sepsis,” Dr. Landry explained. He maintained that vasopressin acting synergistically with endogenous or exogenous catecholamines can stabilize or increase blood pressure. Although the hormone is an antidiuretic, it has been shown to increase urine output and improve creatinine clearance in shock patients. Vasopressin does not alter cerebral constriction or coronary flow, nor does it influence pulmonary arterial pressure, making it a good agent for patients with pulmonary hypertension and for those in whom a pulmonary vasoconstrictor is contraindicated.

Dr. Landry said that the agent has been shown in several published reports to increase blood pressure without substantially depressing heart function or increasing carbon dioxide tension in the gastric mucosa. Another upside to vasopressin is that it diminishes the deleterious effects of catecholamines, including decreased cardiac output, compromised renal blood flow, and increased pulmonary vascular resistance. Dr. Landry did caution that the physiologic end points used in studies do not always correlate with clinical outcomes. “Physiology, while important, is not sufficient,” he explained, “and yet a few patients with lethal sepsis have survived after vasopressin administration.” Thus, he believes that researchers should not be deterred from interpreting the results of vasopressin studies favorably for selected patients pending the results of outcome trials. Dr. Landry noted that Dr. Russell, before starting his trial, used vasopressin in just this way.

“What factors might modulate a decision to give vasopressin in septic shock?” asked Dr. Landry. He maintained that poor distal limb perfusion, hyperbilirubinemia, and acute cardiac or bowel ischemia would be contraindications for the use of vasopressin. On the other hand, “sepsis complicated by oliguria and impending hemodialysis, with the prospect that you might be able to taper norepinephrine,” might be a good indication for administering the agent.

Dr. Landry believes that giving vasopressin “would be justified in patients with a very high hemodynamic mortality.” After all, “you don’t have much to lose, and the potential benefits outweigh the risks,” he reasoned. For patients with a moderately high risk of death, he considered the prospect of using vasopressin to be an ethical decision. When the mortality risk is moderate, he urged caution. “You don’t want to do harm,” he noted. However, administration may be appropriate for a patient with a clinical indication for vasopressin use (eg, impending renal failure or pulmonary hypertension) in addition to sepsis. If the patient is at low risk of death, there would be no compelling reason to administer the drug.

MORE CAUTION NEEDED

Dr. Russell, a Professor of Critical Care Medicine at the University of British Columbia in Vancouver, urged caution in using vasopressin. “It is very rare in medicine that we find a molecule that is ubiquitously beneficial and has no risk. [Vasopressin] has some risk, particularly in selected patients,” he warned.

Sepsis is a major public health problem, said Dr. Russell, not only because mortality remains high but also because there has been a 50% increase in septic shock incidence over the past seven years. However, he maintained that the vasopressin question is currently in a state of “clinical equipoise”—some studies show a benefit, others demonstrate deleterious effects, and there are no outcome studies. With clinical equipoise, Dr. Russell argued, “it is a time for restraint.”

Dr. Russell agreed that endogenous vasopressin levels are reduced in sepsis. “Sepsis patients are uniquely sensitive to vasopressin,” he stated. He admitted that the drug occasionally appears to increase survival among his group’s patients. Nevertheless, he maintained that it “should not be routine first therapy or second therapy.” Vasopressin may be good in extreme cases of sepsis, but it should not be used routinely because evidence of its safety and efficacy is lacking.

He cited his own group’s retrospective study that examined the effects of vasopressin on 50 patients with septic shock.² The agent was associated with two favorable outcomes: It increased mean arterial pressure and urine output. However, the mortality rate in his study was 85%. Dr. Russell argued that survivor bias may have played a role in the results. Once the nonsurvivors died, they could no longer contribute to the data pool; thus, there may have been a natural bias for some outcomes to appear to improve. In another randomized blinded study from his center, vasopressin decreased norepinephrine requirements and increased urine output and creatinine clearance; however, like many other studies of vasopressin, the infusion and study period were only a few hours.³

Dr. Russell also cited evidence that vasopressin, at least in high doses, could be harmful. The drug has been known to cause necrotic ischemia at the infusion site. “You don’t want this thing to run interstitial,” he said, because vasopressin is a potent vasoconstrictor in the interstitial space. Vasopressin has also been reported to worsen gut mucosal acidosis.

He also cautioned that some drugs, while in development, can seem to benefit patients. In clinical practice, however, they may be found to worsen outcome. Dr. Russell used the example of nitric oxide synthase inhibitors, which in initial studies were shown to increase blood pressure over time in sepsis patients. However, later investigations revealed that they increased mortality. “It’s an example of the yin-yang of a drug that is similar to vasopressin. The dose is critical; low doses might be beneficial. High doses might actually be detrimental.” He called for longer trials, because current studies observe patients only up to 24 hours posttreatment.

THE VASST STUDY

Dr. Russell and his group currently have a study underway, the Vasopressin and Septic Shock Trial (VASST). They hypothesize that compared with norepinephrine, low-dose vasopressin (0.03 units/min) will increase 28-day survival from 40% to 50% in sepsis patients. So far, there have been no safety issues reported in the trial.

—Tamara Gibb

References
1. Landry D, Russell J. Pro/con: Vasopressin in the treatment of vasodilatory shock. Presented at: 33rd Critical Care Congress; February 23, 2004; Orlando, Fla.
2. Holmes CL, Walley KR, Chittock DR, et al. The effects of vasopressin on hemodynamics and renal function in severe septic shock: a case series. Intensive Care Med. 2001;27:1416-1421.
3. Patel B, Holmes C, Russell JA, Walley KR. Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology. 2002;96:576-582.

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