Botulinum Toxin A for the Treatment of Sympathomimetic Pressor-Induced Digital Hand Ischemia in the Critically Ill Intensive Care Unit Patient

Abstract

Vasopressor-induced ischemia of the hand, while relatively rare, is a severe complication in critically ill intensive care unit (ICU) patients requiring high concentrations of sympathomimetic pressors and often results in digit necrosis and amputation. Currently, there are no widely accepted approaches for treating this cause of peripheral digital ischemia. Case reports have demonstrated that reducing the concentration of vasopressors that patients are given may reverse the progression of ischemic events prior to necrosis. While this approach is at odds with the principle of “life over limb,” it demonstrates that digit necrosis can be reversed, resulting in improved outcomes. Here, we present a therapeutic strategy for treating digital limb ischemia in the septic ICU patient without the need to lower systemic vasopressor dose by using locally injected botulinum toxin A into ischemic hands.

Case Study

This is the case of a 73-year-old male with a medical history significant for aortic root replacement and atrioventricular repair, a repaired abdominal aortic aneurysm, and coronary artery disease status post coronary artery bypass graft. On admission, the patient was found to have an ascending aortic arch hematoma and a pseudoaneurysm requiring total open aortic arch replacement. His hospital course included operative take back procedures for thoracic exploration and washout complicated by intraoperative ventricular fibrillation and ventricular tachycardia. In the intensive care unit (ICU), the patient developed acute vasoplegic and cardiogenic shock requiring an Impella assistive cardiac pump, and extracorporeal membrane oxygenation (ECMO).

Additionally, he received concurrent treatment with 3 intravenous sympathomimetic pressors (vasopressin, norepinephrine, epinephrine), which resulted in progressive ischemia of the digits of his right and left hands (Figure 1). Plastic surgery was consulted for treatment of his bilateral hand digit ischemia.

Figure 1.

Peripheral ischemia immediately prior to botulinum toxin A injection, showing bilateral distal ischemia in digits 1 through 5 of both hands. Right hand (a and b) and left hand (c and d).

At the time of evaluation, the patient had been receiving intravenous epinephrine (0.035-0.18 mcg/kg/min) and norepinephrine (0.04-0.2 mg/kg/min) for 6 days. After careful evaluation of the blue, cold, and ischemic digits, the decision was made to proceed with a treatment protocol of bilateral injections of botulinum toxin A (Botox, Allergan Dublin, Ireland). In brief the protocol involves 100-units of botulinum toxin A injected in divided doses of 7 to 10 units per injection, into the palm and distal palmar arch areas with injection sites at the base of the digits just distal to palmar crease and in the perivascular space surrounding the radial and ulnar artery. This was performed in both the right and left hands (50 units/hand) of our patient.

Digital ischemia was evaluated by the plastic surgery team every 2 days, and comparative images were taken of both hands. A third sympathomimetic agent, vasopressin, was added for progressively worsening hypotensive cardiogenic shock. By post Botox treatment day 10, and while still on pressors, ischemia of the left hand had nearly resolved. In the right hand, ischemia of the first 2 digits resolved, while ischemia progressed to partial tip necrosis in the left-hand digits 3 through 5 (Figure 2).

Figure 2.

Peripheral ischemia 10 days post botulinum toxin A injection into the perivascular areas of the right (a and b) and left (c and d) hands. Images show the digital ischemia having nearly resolved on the patients left. Ischemia on the right resolved in digits 1 and 2, and progressed to necrosis in digits 3 through 5. After botulinum toxin A injection, vasopressin was added as a third sympathomimetic for progressively worsening hypotensive shock.

Discussion

Botulinum toxin A (Botox, Allergan Dublin, Ireland) is a neurotoxin derived from the anaerobic gram-negative bacteria Clostridium botulinum. Classically botulinum toxin acts on presynaptic motor neurons by inhibiting the release of acetylcholine (ACh) into the synapse. This occurs through cleavage of the SNAP-25 protein, thereby preventing vesicular fusion with the cell membrane. ¹

Despite being one of the most potent peptide toxins described, Botox has a favorable safety profile and effectively treats several disorders, including infantile strabismus, overactive bladder, cervical dystonia, and chronic migraines.^2-5 Furthermore, because of its large molecular size, it has a low diffusion rate and has a long active half-life at sites of injection. ⁶

More recently, Botox has been described for the treatment of vasospastic disorders of the hand, particularly Raynaud’s disease.^7,8 Multiple studies testing the benefit of Botox on Raynaud’s demonstrated that perivascular injections effectively increase local blood flow, reduce pain, and improve distal ulcer healing.^9-11 Neumeister et al in 2009 demonstrated that patients have up to a 300% increase in blood flow within 15 minutes of injection. ¹⁰ Similarly, over 80% of patients experienced an almost immediate reduction in pain. The rapid onsets of these therapeutic effects is at odds with the classic mechanism of Botox, which takes up to 3 days to reach efficacy. ⁶ Because of this, it has been proposed that Botox may regulate neuronal function through non-cholinergic pathways. Stone et al in 2012 found that both botulinum toxin and adrenergic inhibitors have similar effects on vasodilation in mice when given alone. However, there was no synergistic benefit when administered together, suggesting Botox may affect vasodilation through an adrenergic (α1/α2 receptor) mechanism. ¹² These alternative mechanisms have been proposed but have not been fully described.

To build on these findings, we recently demonstrated the therapeutic effect of Botox for treating patients with impending distal necrosis secondary to crush injuries, arterial illicit drug injections, and iatrogenic causes. ¹³ In the current report, we further demonstrate the efficacy of Botox for treating pressor-induced digital ischemia in an ICU patient. It is unclear in this case why resolution was seen fully in the left hand but only partially in right hand. It is possible that by the time Botox was injected, day 6 of vasopressor use, the left hand had sustained an irreversible degree of hypoxic injury. It is important to note that, because this was a case study it lacks controls and the results could be secondary to other factors. Supporting the role of botulinum toxin in treating pressor induced ischemia, Stoehr et al in 2021 demonstrated similar therapeutics effects after injecting 50 units into the nose of a patient with pressor-induced nasal tip ischemia. ¹⁴ To date, there have been no controlled clinical trials looking at the effects of botulinum toxin A on pressor-induced ischemia.

Because of the highly localized effects of botulinum toxin A, we do not predict that this therapy will counteract the intended effects of systemic pressors. Supporting this, there is no evidence that botulinum toxin results in hypotension. Further studies are warranted to test the efficacy of this intervention as both a therapeutic and as a preventative measure in ICU patients requiring high doses of sympathomimetics.

In summary, we believe that botulinum toxin A injections in critically ill ICU patients may be a way to save digits and without curtailing intravenous vasopressor use.