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* From the Intensive Care Unit, Salmaniya Medical Complex, Ministry of Health, Manama, Kingdom of Bahrain.
Correspondence to: Mariam A. Al-Ansari, MD, Consultant Intensivist, Intensive Care Unit, Salmaniya Medical Complex, Manama, PO Box 12, Kingdom of Bahrain; e-mail: dr_mariam5{at}hotmail.com
A 26-year-old sickle cell disease patient presented to the accident and emergency department with 1-day history of headache, vomiting, and confusion. Cardiopulmonary resuscitation was initiated for unobtainable BP. He was then shifted to the ICU.
A physical examination revealed a cyanotic face with mottled and cool extremities. Confluent satellite cutaneous purpura was present on the hands and feet. Temperature was 38.8°C, heart rate was 140 beats/min, and arterial pressure was 90/45 mm Hg while the patient received high doses of norepinephrine. However, the large arterial pulses of the involved extremities were all normal (Fig 1 ).
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Forty-eight hours later, the patient was conscious, was not receiving inotropic drugs, and receiving minimal ventilatory support. More rashes appeared on the proximal part of the extremities with some lesions progressing to areas of skin necrosis. The patient started complaining of severe pain in the lower extremities. An examination showed painful, indurated, well-demarcated purple papules and hyperesthetic digits with a bluish-black hue. The pulses of both dorsalis pedis arteries were still palpable. (Fig 2 ).
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Diagnosis: Sepsis-induced purpura fulminans with impending symmetrical peripheral gangrene
Purpura fulminans (PF) is a life-threatening disorder of acute onset that is characterized by cutaneous hemorrhage and necrosis caused by disseminated intravascular coagulation (DIC) and dermal vascular thrombosis. Typically, infectious PF is an acute illness. It occurs only rarely in the course of infections with organisms other than meningococcemia.
Staphylococcus PF is a newly emerging illness. A recent report described five patients with staphylococcal sepsis-induced PF. Four cases were caused by methicillin-susceptible strains. Three patients died. Of the two patients who survived, one required amputation of both legs below the knee. All strains produced toxic shock syndrome toxin-1 or staphylococcal enterotoxin. These toxins initiate multiple inflammatory pathways, including the procoagulant cascade, which, in its most severe form, manifests as PF.
A total of 40 to 70% of patients with sepsis-associated PF could die. The mortality rate in patients with PF has generally decreased with better supportive care and new treatments. However, it remains a disabling condition, often requiring major amputations.
Lesions of PF are similar regardless of the precipitating condition like warfarin-induced or heparin-induced skin necrosis, thrombotic thrombocytopenic purpura, cryoglobulinemia, antiphospholipid syndrome, or paroxysmal nocturnal hemoglobinuria. DIC distinguishes PF from other forms of skin necrosis. All cases of PF involve a shift from a state favoring anticoagulation therapy to a disease state of overwhelming procoagulation. Its cardinal manifestations are the presence of circumscribed ecchymosis of the skin and symmetrical gangrene of the extremities with coagulation abnormalities suggestive of DIC. The histopathologic hallmarks of PF are dermal vascular thrombosis and secondary hemorrhagic necrosis. The distal extremities are involved in a symmetrical manner, probably due to fact that there are fewer collateral channels for tissue perfusion at the time of circulatory collapse. The lesions could progress to necrosis with extension into the subcutaneous tissue including muscle and bone. Often, surgical debridement, skin grafting, or limb amputation will be required.
Symmetrical peripheral gangrene (SPG) has been reported in patients with a multitude of medical conditions such as DIC, infections, and use of vasopressors (eg, dopamine, epinephrine, or norepinephrine), to name a few. Among the infections, meningococcal, streptococcal, Escherichia coli, and pseudomonal infections have been reported to cause it. It is a rare but dreadful complication of septicemia, with a high mortality rate (up to 40%). About half of the patients who survive require amputation of the affected limb. Being sicker with asplenia, our patient was at risk of S aureus PF. Other aggravating factors include immunosuppression, diabetes mellitus, renal failure, and use of vasopressors. SPG should be suspected at the first sign of marked coldness, pallor, cyanosis, or pain in the extremity, as the condition can progress rapidly to frank gangrene requiring amputation. The ischemic changes begin distally and may progress proximally to involve the entire extremity. These changes are not ordinarily preceded by demonstrable peripheral vascular occlusive disease and may be associated in the early stages with intact distal pulses because the large vessels are often spared. Early recognition and immediate discontinuation, if possible, of vasopressor therapy (as it aggravates the low-flow state by enhancing vasoconstriction) and vigorous therapy for sepsis are essential components of SPG management.
Prior reports of PF have documented the depletion of protein C. It is a serine protease and natural anticoagulant that binds endothelial surface thrombomodulin in the presence of excess thrombin to produce activated protein C. Activated protein C then interacts with protein S to inhibit factors Va and VIIIa, thereby limiting thrombosis. During sepsis-induced DIC, much of the protein C is complexed with inhibitors and cannot be activated. Sepsis may also inhibit the activity of thrombomodulin, which is necessary to activate protein C. The potential benefit of activated protein C should be considered since it has been shown to be effective in patients with severe sepsis presenting with PF. Other measures that might help in the treatment of patients with SPG are sympathetic blockade, IV nitroprusside therapy, topical nitroglycerine ointment, local or IV infusion of an 
-blocker, and IV infusion of prostaglandin.
Meningococcemia is more predisposed than other types of bacteremia to cause PF and SPG. However, reported cases of S aureus PF suggest that it can lead to an identical clinical syndrome. On the basis of this, it may be recommended that patients who present with PF receive antibiotic therapy active not only against Neisseria meningitidis and streptococci, but also against S aureus. Consideration should also be given to the early administration of activated protein C (ie, drotrecogin) in an attempt to minimize purpuric skin injury and to down-regulate the inflammatory cascade before irreparable tissue injury occurs.
In the present patient, therapy with activated protein C (drotrecogin 24 mg/kg/h IV infusion for 96 h) was initiated. The purpura stabilized and started healing spontaneously. Only the right middle toe had to be amputated. He was transferred to the ward after a stay of 4 days in the ICU.
Clinical Pearls
Footnotes
The author has reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Received for publication July 13, 2006. Accepted for publication August 3, 2006.
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