Asymmetrical digital gangrene from standard-dose noradrenaline: A rare case report

INTRODUCTION

Noradrenaline is a potent α1-adrenergic receptor agonist widely utilized as a first-line vasopressor in patients with distributive shock and hypotensive states.^[1] While highly effective in maintaining hemodynamic stability, noradrenaline can cause significant peripheral vasoconstriction, leading to tissue ischemia and necrosis. Peripheral gangrene secondary to vasopressor therapy is a rare but serious complication, with a reported incidence of limb necrosis at around 0.25%.^[2] Most cases present as symmetrical bilateral involvement commonly affecting the digits of hands and feet.^[2-8]

The pathophysiological mechanism underlying vasopressor-induced peripheral gangrene involves intense arteriolar vasoconstriction, microcirculatory occlusion, and potential thrombotic complications.^[5] The development of gangrene typically occurs in patients with prolonged infusion periods, high doses, pre-existing peripheral vascular disease, or underlying coagulopathy. However, cases have been documented even with standard dosing regimens in previously healthy individuals, suggesting individual susceptibility factors play a crucial role. We present a rare case of asymmetrical digital gangrene involving only the hands following standard-dose noradrenaline therapy in a previously healthy patient with septic shock.

CASE REPORT

A 34-year-old male with no known comorbidities presented to the emergency department with a 5-day history of high-grade fever, productive cough, and progressive dyspnea. He had no history of smoking, diabetes mellitus, peripheral vascular disease, Raynaud’s phenomenon, coagulopathy, or autoimmune disorders. On examination, he was febrile with a temperature of 39.2°C, tachycardic with a heart rate of 128 beats per minute, tachypneic with a respiratory rate of 32 breaths per minute, and hypotensive with blood pressure of 78/46 mmHg and a mean arterial pressure of 56 mmHg. Oxygen saturation was 88% on room air. Physical examination revealed decreased air entry and coarse crepitations in the right lower lung zone with warm extremities, palpable pulses bilaterally, and a capillary refill time of 3 seconds. Chest radiography demonstrated right lower lobe consolidation consistent with community-acquired pneumonia.

Laboratory investigations revealed a white blood cell count of 18,500/µL, C-reactive protein of 245 mg/L, procalcitonin of 8.2 ng/mL, and serum lactate of 4.8 mmol/L. Coagulation studies showed prothrombin time of 16.2 seconds, activated partial thromboplastin time of 38 seconds, platelet count of 165,000/µL, fibrinogen of 420 mg/dL, and D-dimer of 2.8 mg/L. Blood and sputum cultures were obtained. The patient was diagnosed with severe sepsis with septic shock secondary to community-acquired pneumonia.

The patient was immediately started on broad-spectrum antibiotics along with aggressive fluid resuscitation. Despite initial fluid resuscitation totaling 3 L of normal saline over 2 hours, the patient remained hypotensive with a mean arterial pressure below 65 mmHg. He was transferred to the intensive care unit, where noradrenaline infusion was initiated. Table 1 outlines the vasopressor dosing regimen and timeline of events. Blood cultures subsequently grew Streptococcus pneumoniae sensitive to the antibiotic regimen. The patient required mechanical ventilation for acute respiratory distress syndrome and continued vasopressor therapy for a total of 96 hours.

On day 3 of noradrenaline therapy, approximately 72 hours after initiation, the patient developed painful erythematous lesions over both hands. Initial examination revealed cold extremities with delayed capillary refill exceeding 5 seconds in the affected digits, though radial pulses remained palpable bilaterally. The lesions progressed rapidly over the next 24 hours to well-demarcated gangrenous changes. By day 4, the right hand demonstrated complete dry gangrene of the index finger with black discoloration and clear demarcation at the proximal interphalangeal joint, severe gangrenous changes involving the entire middle finger with mummification, and dry gangrene with eschar formation of the ring finger extending to the distal interphalangeal joint, while the thumb and little finger were completely spared [Figure 1]. The left hand showed gangrenous changes with dark discoloration of the middle finger, with the index finger, ring finger, thumb, and little finger completely spared. Both lower extremities appeared normal with warm feet, palpable pedal pulses, and normal capillary refill in all toes with no evidence of ischemia or discoloration.

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Figure 1:

Clinical photograph demonstrating asymmetrical digital gangrene. The right hand shows severe gangrenous changes involving the index, middle, and ring fingers with mummification and clear demarcation lines, and the left hand shows gangrenous involvement of the middle finger.

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Given the unusual presentation, additional investigations were performed, including Doppler ultrasound of upper extremities, which revealed patent radial and ulnar arteries bilaterally with reduced flow in digital arteries of affected fingers, but no evidence of large vessel thrombosis. Echocardiography showed normal left ventricular function with an ejection fraction of 55% and no vegetations or intracardiac thrombi. Autoimmune workup, including antinuclear antibody, anticardiolipin antibodies, and rheumatoid factor was all negative. Thrombophilia screening, including protein C and S, factor V Leiden, and prothrombin gene mutation, was within normal limits or not detected.

The noradrenaline infusion was immediately discontinued upon recognition of the gangrenous changes on day 4. Hemodynamic stability was maintained through careful fluid management and transition to vasopressin at 0.03 U/min for 48 hours as an alternative vasopressor support. The patient was started on anticoagulation therapy with enoxaparin 60 mg subcutaneously twice daily for 7 days, chosen for reliability in critically ill patients, then transitioned to apixaban 5 mg twice daily after renal function normalization, along with aspirin 75 mg once daily. Topical care consisted of silver sulfadiazine and zinc sulfate cream applied twice daily to affected areas with interdigital padding and sterile dressings. Multimodal analgesia was provided with intravenous paracetamol, tramadol, and pregabalin. Local vasodilator therapy was not administered as the gangrenous changes were already well-established with clear demarcation by the time of recognition, suggesting irreversible tissue loss.

Progressive demarcation of gangrenous tissue occurred over the following weeks. The patient showed gradual improvement with resolution of septic shock by day 7, successful weaning from mechanical ventilation on day 10, and normalization of inflammatory markers by day 14 with lactate of 1.2 mmol/L and procalcitonin of 0.8 ng/mL. Plastic surgery consultation was obtained on day 8, and conservative management was chosen to allow clear demarcation. Autoamputation of affected digits occurred progressively, with the right middle finger undergoing complete autoamputation at 3 weeks, the right index and ring fingers at 4 weeks, and the left middle finger showing partial autoamputation of the distal portion at 4 weeks. The total intensive care unit stay was 14 days, with total hospital stay of 32 days. The patient was discharged with residual stumps healing satisfactorily, and occupational therapy was initiated for hand function rehabilitation. At 3-month follow-up, complete wound healing was achieved with functional hand assessment showing the ability to perform activities of daily living with adaptation, no recurrence of ischemic complications, and successful return to modified work duties.

Upon regaining consciousness on day 5, the patient expressed shock and disbelief, stating, “I came in with pneumonia and now I’m losing my fingers.” As a mechanic and sole breadwinner, he experienced significant anxiety about his livelihood and required psychological support during the intensive care unit (ICU) stay. His wife initially felt guilty, believing the treatment had caused harm, but family counseling sessions helped them understand the life-saving nature of vasopressor therapy and the rarity of this complication. As recovery progressed, the patient demonstrated resilience, stating, “I’m grateful to be alive. My wife and children need me, and I can learn to adapt.” He actively engaged in occupational therapy and appreciated the multidisciplinary approach. At the 3-month follow-up, he had successfully returned to modified work duties using adaptive tools. The patient emphasized: “If my case can help doctors watch for this earlier in other patients, then something good comes from what happened to me.” The family expressed gratitude for transparent communication throughout treatment, which helped them cope with the outcome.

DISCUSSION

This case presents several unique features that distinguish it from typical presentations of vasopressor-induced peripheral gangrene. The most striking aspects are the asymmetrical distribution pattern, exclusive upper extremity involvement with complete lower limb sparing, and occurrence with standard therapeutic dosing in a patient without traditional risk factors.

The pathogenesis involves α1-adrenergic receptor stimulation, causing intense arteriolar vasoconstriction and microcirculatory occlusion.^[1,2,5] In septic shock, additional factors contribute, including endothelial dysfunction from bacterial endotoxins, procoagulant state with coagulation cascade activation, microthrombosis with platelet plugging, and systemic inflammatory response causing further vascular injury.^[8] These sepsis-related changes, combined with noradrenaline’s vasoconstrictive effects, likely created conditions favoring peripheral ischemia.

The occurrence of severe gangrene in this patient without traditional risk factors suggests complex individual susceptibility mechanisms. Potential explanations include adrenergic receptor polymorphisms in α1-adrenergic receptor genes (ADRA1A, ADRA1B, ADRA1D) that may result in differential receptor density or signal transduction efficiency, leading to exaggerated vasoconstrictive responses to standard doses.^[9] Endothelial nitric oxide synthase (eNOS) polymorphisms affecting NO production could impair vasodilatory capacity.^[10] Subclinical prothrombotic states from mild thrombophilias, though not detected in standard screening, may become clinically significant during vasopressor therapy.^[5] Microvascular anatomical variations, including incomplete palmar arch or variant digital artery collateral circulation, could explain differential finger involvement, as incomplete collateral vessels may fail to compensate when primary digital arteries undergo severe vasoconstriction.^[11] Sepsis-induced endothelial glycocalyx degradation increases microvascular permeability and impairs endothelial-mediated vasodilation, potentially creating vulnerable zones in certain vascular beds.^[12] Individual differences in baseline sympathetic tone and regional autonomic innervation patterns could affect local vascular responses^[13] while subclinical microvascular rarefaction may compromise perfusion reserve.^[14]

Table 2 provides a structured comparison of reported cases demonstrating the rarity of asymmetrical presentation in vasopressor-induced peripheral gangrene. Most reported cases demonstrate bilateral symmetrical involvement, making our asymmetrical pattern highly unusual.^[2-8] The differential involvement with three fingers on the right hand versus one on the left suggests complex interactions between individual vascular anatomy, regional receptor sensitivity variations, and local hemodynamic factors. Though echocardiography was negative for cardiac sources, transient microemboli from endothelial injury during sepsis may have distributed asymmetrically to digital vessels. Differential compression or positioning of upper extremities during prolonged ICU stay may have affected regional perfusion, though radial pulses remained palpable bilaterally. The complete lower extremity sparing is particularly noteworthy, as most literature describes predominant foot involvement.^[2-8] This may reflect individual vascular territory differences, cardiac output redistribution affecting upper limb circulation, or gravitational effects from elevated positioning. Doppler ultrasound findings of patent major vessels but reduced digital flow support a microcirculatory rather than large vessel occlusive process.

The development of severe gangrene with noradrenaline dosing of 0.08 to 0.11 mcg/kg/min is particularly noteworthy as this falls within standard clinical recommendations (0.1-2 µg/kg/min) and is considerably lower than doses typically associated with peripheral gangrene complications.^[1] Furthermore, the patient lacked traditional predisposing factors, including peripheral vascular disease, diabetes mellitus, smoking history, pre-existing coagulopathy, advanced age, and prolonged high-dose vasopressor therapy. This emphasizes that peripheral gangrene can occur unpredictably even in optimal circumstances, highlighting individual susceptibility factors that are not yet fully understood.

Although vasopressor-induced ischemia was the most likely diagnosis, other conditions were considered and systematically excluded, including septic emboli ruled out by negative echocardiography, disseminated intravascular coagulation excluded based on normal fibrinogen and platelet counts, vasculitis made unlikely by negative autoimmune workup, thrombotic thrombocytopenic purpura excluded by normal platelet counts and absence of hemolysis, and inherited thrombophilias excluded by negative screening tests. The temporal relationship with noradrenaline therapy, presence of septic shock as a known risk factor, and exclusion of alternative diagnoses supported the diagnosis of vasopressor-induced peripheral gangrene.

Management of established peripheral gangrene focuses on limiting further tissue loss and managing complications, though the timing and efficacy of vasodilator rescue therapies remain controversial. Therapies that may slow or reverse ischemia in earlier stages include sympathetic blockers, intravenous vasodilators, local injection of alpha-blockers, intravenous alpha-adrenergic antagonists, infiltration with phentolamine, phosphodiesterase inhibitors, topical nitroglycerin ointment, and epoprostenol or iloprost.^[8] However, most vasodilator therapies are only effective if initiated during reversible ischemia before tissue necrosis develops, and once demarcation occurs, tissue loss is irreversible. Systemic vasodilators may worsen hemodynamic instability in shock states, creating a therapeutic conflict between peripheral and vital organ perfusion. No consensus exists on which agent to use, optimal dosing, or duration of therapy, with most evidence coming from case reports rather than controlled trials. In this case, vasodilator interventions were not pursued as the gangrenous changes were already well-established at recognition, suggesting irreversible tissue loss. However, this highlights that earlier recognition during the erythematous/ischemic phase (day 3) rather than after established gangrene (day 4) might have allowed therapeutic interventions to salvage tissue.

This case provides several important clinical lessons. Peripheral perfusion should be monitored closely in all patients receiving vasopressor therapy, regardless of dose or risk factors, through regular examination of extremities for color, temperature, capillary refill, and pulses to allow earlier intervention. Future protocols may benefit from incorporating objective perfusion monitoring technologies to detect early ischemic changes before clinical manifestations. Complications can occur even with standard dosing in patients without traditional risk factors, demonstrating unpredictable individual susceptibility. In patients developing early ischemic signs, clinicians should consider switching to alternative vasopressor agents such as vasopressin or angiotensin II. Early involvement of vascular surgery, plastic surgery, and rehabilitation services in a multidisciplinary approach optimizes outcomes for affected patients.

CONCLUSION

This case demonstrates that asymmetrical peripheral gangrene can occur following standard-dose noradrenaline therapy in previously healthy patients with septic shock. The atypical presentation challenges conventional understanding of vasopressor-induced complications and emphasizes the necessity for vigilant monitoring of peripheral perfusion in all patients receiving vasopressor therapy, regardless of dose or presence of traditional risk factors. Further research into genetic, microvascular, and molecular susceptibility factors is warranted to identify high-risk patients and develop preventive strategies.