Respiratory Arrest Associated with Polymyxin B in a Lung Transplant Patient
Polymyxin antibiotics, including colistin (polymyxin E) and polymyxin B (PMB), were first introduced in the 1950s. These drugs did not undergo the rigorous drug development procedures that are standard today. However, their clinical use has seen a resurgence in recent years, particularly as salvage therapy for infections caused by multidrug-resistant (MDR) gram-negative bacteria (GNB). In lung transplant (LT) patients, MDR-GNB infections, primarily caused by pathogens such as Pseudomonas aeruginosa and Klebsiella pneumoniae, have become increasingly prevalent. This has led to a renewed reliance on these older antibiotics. Despite their effectiveness, the use of polymyxins is not without risks. One of the most severe and life-threatening complications associated with PMB is neuromuscular blockade, which can lead to respiratory paralysis. This article presents a detailed account of a rare case of respiratory arrest induced by PMB in a 67-year-old lung transplant patient.
The patient, a 67-year-old male with no significant past medical history, underwent a left single lung transplant in October 2018 for end-stage idiopathic pulmonary fibrosis. Postoperative management included the discontinuation of all anesthetics and sedatives three days after the surgery. Antimicrobial prophylaxis was administered according to the hospital’s standard protocol, which included cefoperazone-sulbactam/piperacillin-tazobactam, vancomycin, ganciclovir, sulfadiazine and trimethoprim tablets, caspofungin, and inhaled amphotericin. Vancomycin was discontinued four days later. The patient’s immunosuppressive regimen consisted of oral tacrolimus, mycophenolate mofetil, and methylprednisolone. Prophylactic anticoagulant therapy with low-molecular-weight heparin was also administered. The patient was transferred from the intensive care unit to the ward on the third postoperative day and was able to walk without oxygen assistance.
On the 14th postoperative day, the patient developed a productive cough, leukocytosis, and elevated procalcitonin levels. A chest X-ray revealed moderate infiltrates in the left lower lobe. Endoscopic examination showed endobronchial erythema and purulent secretions, with cultures positive for carbapenem-resistant Acinetobacter baumannii (CRAB). The CRAB isolate was sensitive only to PMB (minimum inhibitory concentration [MIC] ≤0.5 mg/mL) and tigecycline (MIC = 2 mg/mL). The patient’s serum creatinine level was slightly elevated at 112.9 mmol/L (normal range: 35.0–106.0 mmol/L) before initiating the antimicrobial regimen, which consisted of PMB (25,000 IU/kg, divided into two doses) and tigecycline (100 mg, q12h).
Two days after starting intravenous PMB, the patient experienced mild chest tightness and weakness in both lower limbs. On the third day, approximately 30 minutes after the initiation of a PMB infusion, the patient developed sudden hypercapnic respiratory failure (pH 7.004, PaCO2 83.6 mmHg, and PaO2 105 mmHg on fraction of inspired oxygen [FiO2] 0.5). Non-invasive positive pressure ventilation was attempted but failed, necessitating rapid intubation. The patient recovered quickly and was extubated within 24 hours. However, eight days after the initiation of PMB, the patient experienced a second episode of respiratory failure during another PMB infusion. This episode also required intubation and mechanical ventilation.
Extensive diagnostic workup, including bronchoscopy, cranial computed tomography, chest X-ray, echocardiogram, electrocardiogram, and laboratory tests, ruled out other potential causes of respiratory failure such as pulmonary embolism, pneumothorax, airway congestion, electrolyte disturbances, and neurological conditions like stroke and epilepsy. Ultrasound of the diaphragm muscle revealed thinning and decreased motion amplitude of the bilateral diaphragm. The patient recalled being fully aware but unable to breathe during the episodes. After a thorough review of the patient’s medications, PMB was identified as the likely cause of the respiratory distress, given its known potential to induce neuromuscular blockade. PMB was discontinued, and the patient was extubated without further complications. Sulbactam was substituted for PMB and combined with tigecycline to treat the CRAB infection. The patient was discharged 1.5 months after the lung transplant without any recurrence of respiratory distress.
The increasing prevalence of MDR-GNB infections, particularly in critically ill patients, has made polymyxins a last-resort therapy for severe infections. However, respiratory muscle paralysis is a rare but potentially fatal complication of PMB use. In this case, the patient experienced sudden respiratory arrest twice, both times requiring intubation and mechanical ventilation. The episodes were accompanied by lower limb muscle weakness, consistent with the neurotoxicity of PMB. The Naranjo Adverse Drug Reaction Probability Scale score of 9 indicated a definite relationship between PMB administration and respiratory arrest. The respiratory failure was suspected to be associated with diaphragmatic dysfunction due to neuromuscular blockade.
Several factors may have contributed to the PMB-induced neuromuscular blockade in this patient. First, PMB was newly approved by the Chinese Food and Drug Administration in September 2017 and introduced at China-Japan Friendship Hospital in March 2018, leading to a lack of clarity regarding its optimal use and dosing. Second, therapeutic drug monitoring was not initially implemented, although international consensus guidelines recommend an area under the curve 24-hour target of 50 to 100 mg·h/L to minimize toxicity. Third, the patient had mild renal dysfunction, which may have increased the risk of PMB toxicity. Previous studies have identified renal insufficiency as a significant risk factor for polymyxin-associated neuromuscular blockade. Fourth, the patient was on multiple medications post-transplant, including immunosuppressants, corticosteroids, antimicrobials, and protective drugs, which may have interacted with PMB. Finally, PMB was infused over one hour in this patient, whereas prolonging the infusion time to over two hours in lung transplant patients with multiple concomitant medications warrants further investigation.
In conclusion, this case highlights the potential for severe neuromuscular blockade and respiratory arrest associated with PMB use, particularly in lung transplant patients with renal dysfunction and multiple concomitant medications. Clinicians should be vigilant for signs of neuromuscular toxicity when using PMB and consider therapeutic drug monitoring and adjusted infusion times to minimize the risk of adverse effects. The case also underscores the need for further research into the optimal use of polymyxins in high-risk patient populations.
doi.org/10.1097/CM9.0000000000000826
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