Year : 2023 | Volume
| Issue : 1 | Page : 58-64
COVID-19 associated Mucormycosis (CAM): Implications for perioperative physicians – A narrative review
Anju Gupta1, Bhavana Kayarat1, Nishkarsh Gupta2
1 Anaesthesiology, Pain Medicine and Critical Care, All India Institute of Medical Sciences, New Delhi, India
2 Onco-Anaesthesiology and Palliative Medicine, DRBRAIRCH, AIIMS, India
Onco-Anaesthesiology and Palliative Medicine, DRBRAIRCH, AIIMS, New Delhi
Source of Support: None, Conflict of Interest: None
|Date of Submission||08-Sep-2022|
|Date of Decision||10-Sep-2022|
|Date of Acceptance||11-Sep-2022|
|Date of Web Publication||02-Jan-2023|
Mucormycosis once considered a rare disease with an incidence of 0.005 to 1.7 per million, has become one of the greatest menaces during the coronavirus disease (COVID-19) pandemic. India alone has contributed to nearly 70% of the global caseload of COVID-associated mucormycosis (CAM) and it had even been declared as a notifiable disease. Second wave of COVID-19 pandemic saw a steep rise in the incidence of mucormycosis and these patients have been presenting to anesthesiologists for various surgical procedures due to its primary or secondary sequelae. Rhino-orbito-cerebral mucormycosis (ROCM) is the commonest manifestation and is caused by Rhizopus arrhizus. Injudicious use of corticosteroids in vulnerable patients could have been a major contributing factor to the sudden rise in ROCM during the pandemic. Concerns related to anesthetic management include COVID-19 infection and post COVID sequalae, common presence of uncontrolled diabetes mellitus, possibility of difficult mask-ventilation and/or intubation, various drug therapy-associated adverse effects, and interaction of these drugs with anesthetic agents. Thorough preoperative optimization, multidisciplinary involvement, perioperative care, and vigilance go a long way in improving overall outcomes in these patients.
Keywords: CAM, COVID-19, mucormycotic, perioperative
|How to cite this article:|
Gupta A, Kayarat B, Gupta N. COVID-19 associated Mucormycosis (CAM): Implications for perioperative physicians – A narrative review. Saudi J Anaesth 2023;17:58-64
|How to cite this URL:|
Gupta A, Kayarat B, Gupta N. COVID-19 associated Mucormycosis (CAM): Implications for perioperative physicians – A narrative review. Saudi J Anaesth [serial online] 2023 [cited 2023 Feb 3];17:58-64. Available from: https://www.saudija.org/text.asp?2023/17/1/58/364881
| Introduction|| |
The incidence of superinfection with invasive fungal infections COVID-19 pandemic is 4–13% and mostly due Aspergillosis and Candidemia. Mucormycosis was considered a rare disease, with an incidence of 0.005 to 1.7 per million prior to the pandemic. But the incidence of mucormycosis had increased rapidly during the second wave of the pandemic, with India having contributed to nearly 70% of the global caseload of COVID-associated mucormycosis (CAM) and had even been declared as a notifiable disease., However, unlike the other invasive fungal superinfections, mucormycosis was seen even in patients with mild-to-moderate COVID infection.
Mucormycosis is caused by Zygomycetes that are filamentous and invades blood vessels mostly by Mucorales (Rhizopus, Lichtheimia, Mucor, and Cunninghamella) and Entomophthorales (Conidiobolus and Basidiobolus). Mucormycosis was first described by Paultauf in 1885. The first case from India was reported in 1963.
Rhizopus arrhizus was most frequently identified pathogen associated with CAM in India. Presence of diabetes mellitus (DM), hypoxemia, and irrational use of steroids were independently associated with CAM. Improper antibiotic prescriptions, increased zinc intake, ventilators with defective humidifiers, and use of industrial oxygen all contributed to the outbreak. Mucormycosis is not contagious, and human-to-human transmission has not been documented.
| Methods|| |
Search strategy and selection criteria
To identify articles, key questions were formulated to construct an analytic framework and were searched through PubMed, Embase, and Google Scholar to find relevant articles and identify pertinent literature. A comprehensive literature search was conducted with inclusion criteria related to the anesthetic management of CAM which was specifically geared toward studies and reports that investigated the preoperative assessment and comorbidities in CAM, steroids, antifungal treatment, and its adverse effects and interactions with anesthetic agents, airway management in CAM, other specific anesthesia concerns in CAM patients undergoing surgical procedures, and postoperative management of these patients. Studies published prior to 2012 and those in languages other than English were excluded. Any literature that did not have a full text available was excluded. Keywords searched included “COVID-19,” “SARS-Cov-2,” “Coronavirus,” “COVID,” “Antifungal treatment,” “steroids,” “adverse effects,” “diabetes mellitus,” “complications,” “airway management,” “preoperative assessment,” “anaesthetic concerns,” “anaesthesia,” “perioperative,” and “postoperative management.” The various keywords were joined using Boolean operators “And,” “Or,” and “Not” in various combinations to obtain the relevant articles, which were then carefully screened for eligibility for inclusion in the review. The references of relevant articles were further hand searched. The study designs selected to be included were case–control studies, case studies, case reviews, guidelines, systematic reviews, and meta analysis. This information was extracted and organized in text and tabular form. The search mainly focused on identifying literature that had conducted studies on CAM in relation to anesthetic management and was then narrowed to relevant literature.
This literature review is presented as a qualitative non meta analysis narrative review. The first step in extracting the data was to decide which type of study designs were to be included in this review. Then any publication prior to 2012 was excluded. The next step was to focus on extracting those articles that were related to and supported the core concept of this review while minimizing bias and maintaining the reliability and validity of the data.
COVID-19 associated Mucormycosis (CAM): Pathogenesis
Infection occurs due to either inhalation of spores or contamination of wounds. Large numbers of Mucorales spores are present in hospitals and outdoor air across different seasons. Rhizopusarrhizus leads to “Rhino-orbito-cerebral Mucormycosis” (ROCM) because its large spores get trapped in the nasal epithelium; whereas Cunninghamella sp. has small spores that reach the lower alveoli to cause pulmonary mucormycosis.
Phagocytes are considered the primary host defense against mucormycosis. Patients with poorly controlled DM may have impaired neutrophil function due to acidic pH and hyperglycemia. In addition, high-dose steroids impede with the intracellular killing of the inhaled Mucorales spores. There is some role of upregulation of endothelial glucose-regulated protein (GRP78) receptors due to hyperglycemia that facilitates adhesion and invasion into the nasal sinuses, lungs and brain. Mucorales also sequester iron from the host. Other virulence factors include secreted proteases and a ketone reduction pathway.
Invasion of vascular endothelial cells is responsible for the dissemination of disease from a primary mucormycosis. In patients with ROCM, fungus reaches the paranasal sinuses, sphenopalatine fossa and CNS after initial localization in nasal mucosal. In CNS there may be involvement of the cavernous sinus (approximately 70% of cases), followed by the cribriform plate (22%) and pterygopalatine fossa (12%).
The RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial had shown that low-dose, short-duration dexamethasone reduced mortality in patients with COVID19. Majority of patients with COVID19associated ROCM (76%) had received systemic corticosteroids even with mild COVID 19 not requiring hospitalization. In India, systemic corticosteroids was given in 87% of the patients with CAM, of which 21% patients received them much more than the recommended dose and duration. Corticosteroids, have immunosuppressive action and increase blood glucose levels by promoting gluconeogenesis, proteolysis and lipolysis and by increasing insulin resistance. Injudicious use of corticosteroids in vulnerable patients could have been a major contributing factor to the sudden rise in ROCM during the pandemic.
Clinical presentation and Diagnosis of CAM
Diagnosis – Clinical presentation
There are distinct clinical syndromes that have been associated with invasive mucormycosis i.e. ROCM, gastrointestinal, pulmonary and widely disseminated. However, the hallmark of the disease is angioinvasion and subsequent thrombosis that leads to tissue necrosis and black necrotic eschars. TROCM followed by pulmonary mucormycosis is the most common presentation associated with the COVID 19 pandemic. Cutaneous mucormycosis, generally associated with trauma was rarely seen in COVID 19 infected patients.
The COSMIC study. was showed the mean age of presentation of 51 years with preponderance in males (71%). Facial pain, headache and facial/orbital edema were the most common neurological symptoms. The onset of symptoms usually developed between 10 to15 days after diagnosis of COVID-19. Loss of vision was reported in 20% of cases with <0.1% of patients presenting with altered sensorium.
The initial signs of ROCM include facial pain, nasal congestion, local tenderness, fever, bloody/brown/black discharge, nausea and headache. Patients later presented with an eschar over the nose, chemosis, proptosis, and perforation of palate. Transneuronal spread may lead to involvement of individual cranial nerves (optic nerve, trigeminal nerve, and facial nerve), orbital apex syndrome, cavernous sinus thrombosis and involvement of multiple cranial nerves of one side (Garcin syndrome). In addition, central retinal artery occlusion or posterior ischemic optic neuropathy may contribute to the optic nerve involvement in CAM.
CAM is also associated with neurovascular complications ranging from watershed infarcts to intracranial hemorrhage. There have been reports describing stenosis or complete occlusion of the internal carotid artery. Fungal invasion into the arterial wall could lead mycotic aneurysms and subarachnoid hemorrhage. Other abnormalities like basal meningeal enhancement, areas of cerebritis and cerebral abscesses have also been noted in these patients.
MRI is a good imaging modality to detect mucormycosis infections involving sino-nasal-orbital region and intracranial extension. CT is better in identifying the bony erosion seen in the advanced stages of infection.
MRI imaging findings include thickening of mucosa, opaque paranasal sinuses, hypertrophied nasal turbinates and “black turbinate sign” (nonenhancing soft tissue within the affected turbinate). Extension into the orbit, cavernous sinus, infratemporal fossa, skull base, and intracranial compartment is also noted.
Histopathological examination of tissues with KOH mount will demonstrate characteristic broad aseptate hyphae with a ribbon-like appearance due to folding of hyphae. Mucorales show typical cottony growth and invasion and occlusion of the vessels with appropriate staining.
CAM: Management principles
The management principles guiding the treatment of CAM includes a combination of surgical debridement of necrotic tissues and long-term antifungal treatment, guided by culture reports to prevent relapse. Controlling the underlying predisposing factors such as diabetes, ketoacidosis, corticosteroids intake and any immunosuppressant agents is key in preventing further progression of the disease. Management of mucormycosis is a team effort comprising of the ENT surgeon, ophthalmologist, pathologist, microbiologist, maxillofacial surgeon, anesthetist/intensivist and radiologist.
The key to successful control of mucormycosis resides in early and aggressive surgical resection as per radiological findings. Patients with angioinvasion benefit from higher dose of intravenous therapy, and early surgical debridement. In ROCM infection, early complete debridement of the infected tissues or orbital exenteration improves survival rates. COSMIC study showed debridement of paranasal sinus and orbit reduced death from 52% to 39% in patients with stage 4 disease. Debridement also provides necessary tissue specimens for definite histopathologic diagnosis. Repeated debridement often is necessary in cases of recurrence. However, the timing and definitive role of routine orbital exenteration in ROCM is currently unclear.
Antifungal therapy with amphotericin B (lipid-based formulations), posaconazole, or isavuconazole should be started early [Table 1]. A delay of even more than 6 days may increase mortality rate at 12 weeks two folds. Surgical management along with early, high-dose systemic antifungal therapy, resulted in 1.5-fold times increase in survival rates. It should also be remembered that Mucorales are intrinsically resistant to Azoles, Echinocandins and 5-flurocytosine, and hence should not be used for treatment. There is currently no role for primary antifungal prophylaxis in CAM.
A number of formulations of amphotericin like liposomal, deoxycholate, lipid complex, and colloidal dispersion are available. Liposomal amphotericin B is drug of choice at a dose of 3–5 mg/kg per day in 200 mL of 5% dextrose over 2–3 h for 3–6 weeks. If well tolerated, infusion time can be reduced to 60 min.
The major concern seen with the standard preparation include severe rigors and nephrotoxicity. Initial manifestations include kaliuresis and hypokalemia, followed by fall in serum bicarbonate (renal tubular acidosis) and rising BUN/creatinine. The risk of renal injury can be minimized by appropriate hydration of 500 ml saline.
Posaconazole and Isavuconazole
Posaconazole broader spectrum second-generation triazole that acts by inhibiting the lanosterol-14a-demethylase. It is less affected by common resistance mechanisms such as efflux pumps and point mutations in the target enzyme. Posaconazole is currently available in three formulations. [Table 2]. Routine TDM is strongly recommended for patients with mucormycosis. It should be used with caution in patients with QTc prolongation. It takes around 7–10 days to achieve a steady state 1 μg/mL or higher serum trough concentration of posaconazole is recommended to reduce treatment failure. The important drug interactions with anti-fungal drugs are summarized in [Table 3].
|Table 3: Important drug interactions with antifungal drugs from an anesthesiologists perspective|
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Anesthesia concerns in a patient with CAM
Anesthetic management of a COVID patient with mucormycosis is a formidable challenge. This relates to the following important risks related to their pathogenesis.
Concerns related to COVID infection and Post COVID Sequalae
SARS-CoV-2 infection has the potential to cause multisystem involvement [Table 4]. Evidence suggests a 20–25% increase in 30-day mortality with increased risk of postoperative pulmonary complications in patients undergoing surgery with perioperative COVID-19 infection. The post COVID sequelae can include symptoms due to lasting inflammation, organ damage [Table 4], psychological distress and chronic fatigue. The patients could also be on multiple drugs including steroids, anticoagulants and antiinflammatory monoclonal antibodies (e.g., tocilizumab) as part of their COVID-19 treatment. These factors make the perioperative management of COVID-19 challenging.
Uncontrolled diabetes mellitus
It has been postulated that SARS CoV 2 virus damages islet cells in the pancreatic to result in new onset DM in 20.6% of patients with mild to moderate disease and worsen preexisting DM or DKA. Hoenigl et al. showed that DM accounted for 80% of the cases and concomitant DKA was present in 15–41% patients with a median HBA1c level of 11%. DM, per se, is a recognized high-risk factor for perioperative cardiac events. Patients frequently have co-existing microvascular and macrovascular complications like coronary heart disease, diabetic nephropathy and autonomic neuropathy. They are at an increased risk for surgical site infections as well.
Surgical patients with Type 2 DM with fasting period greater than 1 missed meal develop significant hyperglycemia (CBG >220 mg/dL); and patients with poorly controlled diabetes (HbA1c >8.5%) often require a Variable rate insulin infusion (VRIII). However, the main concern in the perioperative management is to avoid hypoglycemia. Around 22% of patients with DM suffer from at least one episode of hypoglycemia during their hospitalization and are associated with worse outcomes., Hence, meticulous initial assessment and planning are required.
Patients with ROCM usually present with poor dental hygiene and often have a difficult airway. The presence of facial edema, perioral wound, and proptosis can hinder adequate mask ventilation. They often have reduced mouth opening because of jaw erosion and pain. Palatal ulcers may bleed on touch and palatal perforations could contribute to difficult laryngoscopy. Loosening of maxillary teeth is seen in most patients with ROCM. The associated epiglottitis, oroantral fistulas, sub and supra-glottic oedema and joint stiffness due to DM can further make intubation more challenging.
Patients with CAM when they are in infective period, during in-hospital recovery, or even postdischarge. Preoperative evaluation should include enquiring on the presence of a history of DM or associated DKA, compliance to therapy of DM, past history of COVID, preexisting pain in the head and any prior surgical intervention done. The extent of disease based on radiology reports have to be also noted.
Pre-anesthetic evaluation should assess the functional status of the patient, systemic sequelae of SARS-CoV-2 infection and the difficulty of airway anticipated. Evaluation should include a thorough history and clinical examination, including bedside pulmonary function tests like effort tolerance estimation, breath-holding time and measure ambulatory oxygen saturation. Other tests including liver and renal function tests, including serum electrolytes maybe performed, especially in patients receiving antifungal therapy. Further investigations can be individualized based on the patient and the nature and urgency of surgery. Echocardiography can be considered in patients with severe hypoxia, significant cardiac symptoms or ECG reports suggestive of any arrythmias or structural heart disease.
Perioperative optimization of blood glucose with IV insulin is important. Patients in whom DKA may need arterial blood gas measurements, serum electrolyte and serum or urine ketone bodies. Patients may receive low molecular weight heparin or long-acting oral anticoagulants post COVID infection. The decision to stop anticoagulants should be taken after weighing the risk- benefit of stopping the drug.
In patients with prolonged steroid therapy (prednisolone equivalent of >5 mg per day in the last three months), stress dose of corticosteroids should be supplemented as adrenal suppression may lead to perioperative hypotension. A high-risk informed written consent should be based on the patient's clinical condition, the likely need for tracheostomy, and for the surgical procedure that could cause facial disfiguration.
Intraoperative concerns for Endoscopic debridement in CAM
Anesthetic goals include providing effective airway protection along with an immobile visible surgical field with adequate analgesia and patient comfort.
Electrocardiography, oxygen saturation, end-tidal carbon dioxide along with temperature and urine output measurement are essential. Due to limited airway access; long ventilator tubing and extension lines for vascular access are required. Patients often have a central venous due to the perioperative need for intravenous potassium chloride supplementation for the management of hypokalemia caused by the antifungal drugs.
Intravenous induction can be done with titrated doses of any of the induction agents. Isoflurane is preferred inhalational anesthetic agent as it has been reported to inhibit in vitro fungal growth. Succinylcholine should be avoided in patients recovering from prolonged COVID-19 critical illness to prevent any hyperkaliemia due to myopathy.
Management of airway
Patients with ROCM may have difficult mask ventilation and endotracheal intubation. So, a difficult airway cart including supraglottic airways, video laryngoscopes, smaller sized cuffed endotracheal tubes, airway exchange catheters, bougie/stylet with tracheostomy backup must be kept ready.
Preoxygenation is important for safe airway management in the context of active COVID 19 infection, as it reduces the need for facemask ventilation and other aerosol-generating procedures. When administering anesthesia in patients with active infection, the face mask ventilation technique should result in minimal leak. This may include a combination of optimal airway positioning, use of airway maneuvers (chin lift and jaw thrust), use of 'VE hand' position ('vice grip'); use of a two-person technique; early use of airway adjuncts like oropharyngeal airway or supraglottic airway. Various consensus airway management guidelines advocate video laryngoscopy as the preferred technique for tracheal intubation.
The 15° head up position aids in venous decongestion. Every 2.5 cm above the heart correlates with a decrease of arterial blood pressure by 2 mm Hg and improve the endoscopic field of view. Care is to be taken to secure the endotracheal tube to avoid accidental extubation and disconnection. The occlusive dressing/goggles should be used to protect eyes with the lid closed to prevent skin preparation solution from entering the eyes.
Maintenance of anesthesia depth
An appropriate timely use of muscle relaxants with adequate depth of anesthesia is vital for any straining/coughing by the patient. Though hypotensive anesthesia help seduce blood loss, utmost care must be taken to maintain perfusion to the vital organs, especially avoiding any renal insult. Intraoperative bleeding is uncommon; however, blood loss can occur in patients undergoing re-debridement due to disease recurrences.
Perioperative control of blood sugars
The initiation of VRIII must never be delayed once the decision is made on managing the blood sugars with intravenous insulin. The substrate solution (5% dextrose in 0.45% saline, with KCl) along with insulin can be given through a second cannula with one-way valves at a rate of 1–1.25 ml/kg/hour. Blood sugars have to be maintained hourly, in the range of 110–180 mg/dl. Adequate caution is to be taken as VRIII is associated with both hypo- and hyperglycemia, hyponatremia, and hypokalemia. To prevent discontinuation of insulin/substrate solution; additional resuscitative fluids can be given through a separate cannula.
Emergence and reversal
A smooth emergence and extubation will help in preventing an increase in postsurgical bleeding and improve patient discomfort. In a review, it was noted that 28% of patients required postoperative elective mechanical ventilation since the surgery was extensive. Postoperative SICU care may be required in cases of multiple comorbidities with post COVID respiratory issues and to monitor the progress of infection postsurgery.
Patients are at an increased risk of nausea and vomiting and perioperative acute kidney injury (AKI). Postoperative pain can be managed with paracetamol and nonsteroidal antiinflammatory drugs (NSAIDs). Increased serum creatinine level and presence of thrombocytopenia in the postoperative period can point toward the increased mortality in patients with mucormycosis.
| Conclusion|| |
Post COVID-19 mucormycosis patients presenting for surgical procedures pose unique anesthetic challenges due to its systemic manifestations, associated systemic disorders, drug toxicity and interactions, difficult airway, and COVID-19 infection related sequelae. Multidisciplinary management and vigilant perioperative care are required for successful perioperative outcome.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]