Refractory atrial fibrillation with rapid ventricular response as a heralding sign of propofol infusion syndrome in a patient with COVID-19
- 1 Internal medicine, St Joseph Mercy Health System, Ann Arbor, Michigan, USA
- 2 Critical care/Pulmonology, St Joseph Mercy Health System, Ann Arbor, Michigan, USA
- Correspondence to Dr Madiha Naqsh Siddiqui; madihanaqshsiddiqui@gmail.com
Abstract
A woman in her 40s was transferred to the medical intensive care unit due to severe COVID-19 infection causing respiratory failure. Her respiratory failure worsened rapidly, requiring intubation and continuous sedation with fentanyl and propofol infusions. She required progressive increases in the rates of the propofol infusion, as well as addition of midazolam and cisatracurium due to ventilator dyssynchrony. To support the high sedative doses, norepinephrine was administered as a continuous infusion. She developed atrial fibrillation with rapid ventricular response, with rates ranging between 180 and 200 s which did not respond to intravenous adenosine, metoprolol, synchronised cardioversion or amiodarone. A blood draw revealed lipaemia, and triglyceride levels were noted to be elevated to 2018. The patient developed high-grade fevers up to 105.3 and acute renal failure with severe mixed respiratory and metabolic acidosis, indicating propofol-related infusion syndrome. Propofol was promptly discontinued. An insulin-dextrose infusion was initiated which improved patient’s fevers and hypertriglyceridaemia.
Background
Propofol is an intravenous sedative medication that is commonly employed in the intensive care unit (ICU). Its use increased significantly during the COVID-19 pandemic (along with other sedatives) directly contributing to the development of serious side effects such as propofol-related infusion syndrome (PRIS).
Case presentation
A woman in her 40s was transferred to the medical ICU due to severe COVID-19 infection causing respiratory failure.
Her medical history was significant for morbid obesity with a body mass index of 48 kg/m2, quiescent sarcoidosis that was remotely treated with leflunomide, mild sleep apnoea, mixed anxiety/depression and gastro-oesophageal reflux disease. Her past surgical history was notable for transthoracic needle biopsy, cholecystectomy, appendectomy, endoscopic sinus surgery and two caesarean sections. Her medications prior to arrival consisted of buspirone, duloxetine, a levonorgestrel intrauterine device, omeprazole and melatonin. Her allergies consisted of anaphylaxis to codeine and ibuprofen. She was a never-smoker and had completed vaccination with two-dose Moderna COVID mRNA (mRNA-1273) vaccination about 8 months prior.
The patient had presented to the emergency department about 2 weeks prior, having generalised body aches and diarrhoea for 4 days. At the time, she was hypoxic to 90% and required 2 L of oxygen via nasal cannula. Throughout the course of her hospitalisation, the patient was administered courses of remdesivir, dexamethasone and tocilizumab, as well as vitamins C, D and zinc. However, her respiratory failure worsened rapidly, transitioning from oxygen via non-rebreather to high flow nasal cannula to bilevel positive airway pressure (BiPAP) within a matter of days. She was transferred to the ICU for further management.
Investigations
Investigations on admission to the ICU revealed (tables 1–3).
Complete blood count
| White cell count | 6.1×103/µL (×109 /L) |
| Red cell count | 4.44×106/µL (×1012/L) |
| Haemoglobin | 122 g/L |
| Haematocrit | 37.5% |
| MCV | 85 fL |
| MCHC | 325 g/L |
| MCHC | 325 g/L |
| RDW | 14.8% |
| Platelets | 238×103/µL (×109/L) |
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MCHC, Mean corpuscular hemoglobin concentration; MCV, Mean corpuscular volume; RDW, Red cell distribution width.
Basic metabolic panel and electrolytes
| Sodium | 139 mmol/L |
| Potassium | 4.1 mmol/L |
| Chloride | 104 mmol/L |
| CO2 | 27 mmol/L |
| Glucose | 52 mmol/L |
| BUN | 7.5 mmol/L |
| Creatinine | 60.11 µmol/L |
| GFR | 1.57 mL/s |
| Calcium | 1.93 mmol/L |
| Phosphorus | 1 mmol/L |
| Magnesium | 0.82 mmol/L |
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BUN, Blood urea nitrogen; CO2, Bicarbonae; GFR, Glomerular filtration rate.
Arterial blood gas analysis
| pH | 7.414 |
| pCO2 | 5.6 kPa |
| pO2 | 8 kPa |
| HCO3 | 26.8 mmol/L |
| SO2 | 91% |
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HCO3, Bicarbonate; pCO2, Partial pressure of carbon dioxide; pO2, Partial pressure of oxygen; SO2, Oxygen saturation.
Treatment
When assessed on arrival to the ICU, the patient was on high BiPAP settings with an inspiratory positive airway pressure of 20 mm Hg and an expiratory positive airway pressure of 12 mm Hg, with a delta of 8. Even on these settings, she was in respiratory distress; her respiratory rate was 38 breaths per minute, using accessory muscles for breathing. She was emergently intubated with a size 7 endotracheal tube. Continuous sedation was achieved with fentanyl and propofol infusions (initiated at 5 µg/kg/min and titrated to 25 µg/kg/min).
Due to worsening respiratory status despite maximal ventilator settings, aerosolised epoprostenol was initiated to assist with oxygenation. The rate of propofol infusion was increased to 50 µg/kg/min. Prone positioning was used the following day, which required increasing the rate of propofol further to 80 µg/kg/min. Due to ventilator dyssynchrony, midazolam was initiated. Despite this, there was continued dyssynchrony, necessitating the use of cisatracurium. Norepinephrine was administered as a continuous infusion to manage sedation-associated hypotension.
The patient’s course was complicated by the development of hospital-acquired pneumonia. Treatment was initiated with intravenous vancomycin and ceftriaxone.
The next day, the patient developed atrial fibrillation with rapid ventricular response, with heart rates ranging from 180 to 200 beats per minute (see figure 1). Investigations performed at this time revealed the following (tables 4 and 5).
Complete blood count
| White cell count | 23.7×103/µL (×109/L) |
| Haemoglobin | 135 g/L |
| Haematocrit | 41.1% |
| Platelets | 306×103/µL (×109/L) |
Basic metabolic panel, electrolytes and lactate
| Sodium | 132 mmol/L |
| Potassium | 4.4 mmol/L |
| Chloride | 98 mmol/L |
| CO2 | 25 mmol/L |
| Glucose | 7.5 mmol/L |
| BUN | 6.07 mmol/L |
| Creatinine | 60.11 µmol/L |
| GFR | 1.57 mL/s |
| Calcium | 1.9 mmol/L |
| Lactate | 1.3 mmol/L |
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BUN, Blood urea nitrogen; CO2, Bicarbonae; GFR, Glomerular filtration rate.
ECG showing atrial fibrillation with rapid ventricular response, HR 183. HR, heart rate. aVR; augmented vector right, aVL; augmented vector left, aVF; augmented vector foot
Intravenous adenosine was administered to allow for rhythm identification and confirmed atrial fibrillation with rapid ventricular response; this only transiently helped control the tachycardia. Following this, multiple pushes of intravenous metoprolol were administered, without much improvement. Synchronised cardioversion was employed at 200 J two times, again only having a fleeting effect. Norepinephrine infusion was titrated down and substituted by phenylephrine infusion, to theoretically minimise the β−1 activation. Amiodarone 150 mg was then administered, followed by an infusion. Systemic anticoagulation was initiated with enoxaparin.
Meanwhile, this was the sixth day of the patient receiving propofol, maintained at 80 µg/kg/min. A routine blood sample drawn by the bedside nurse was noted to be lipaemic (see figure 2, table 6) with elevated triglyceride levels.
Miscellaneous
| Triglycerides | 22.8 mmol/L |
| Creatine kinase | 5.93 ukat/L |
Lipaemic blood draw.
Furthermore, the patient was noted to have increasing temperatures, being febrile to 38.5°C, which progressively increased to 39.38°C, 39.67°C with a maximum temperature of 40.72°C, largely unresponsive to acetaminophen and external cooling. The patient now also developed acute kidney injury, with laboratory values as follows (table 7).
Basic metabolic panel and electrolytes
| Sodium | 134 mmol/L |
| Potassium | 4.2 mmol/L |
| Chloride | 103 mmol/L |
| CO2 | 21 mmol/L |
| Glucose | 7.1 mmol/L |
| BUN | 13.92 mmol/L |
| Creatinine | 154.7 µmol/L |
| GFR | 0.53 mL/s |
| Calcium | 1.8 mmol/L |
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BUN, Blood urea nitrogen; CO2, Bicarbonae; GFR, Glomerular filtration rate.
Blood cultures were obtained which demonstrated no growth. Despite the amiodarone infusion, the patient had multiple episodes of tachycardia to 180 beats per minute. The case was discussed with cardiology and digoxin was started.
The patient’s refractory atrial fibrillation, hypertriglyceridaemia, elevated creatine kinase level, acute kidney injury and prolonged duration of having received propofol clinically correlated to a diagnosis of propofol infusion syndrome; the sedative infusion was discontinued, and an insulin-dextrose infusion was initiated to theoretically provide substrate for mitochondrial oxidative phosphorylation.
Outcome and follow-up
These measures helped lower the patient’s triglyceride levels to 731 mg/dL, lower the temperature to 38.2°C and lower the heart rate to 111 beats per minute (see figure 3). Unfortunately, the patient developed undifferentiated shock requiring additional pressors (norepinephrine and vasopressin in addition to the phenylephrine infusion). Her course was further complicated by the development of severe mixed respiratory and metabolic acidosis in a short period of time. Given her poor prognosis, the family elected to transition the patient’s care to comfort measures only. The patient was terminally extubated and passed shortly after.
ECG day 2 after cessation of propofol and treatment with insulin/dextrose infusion, showing sinus tachycardia with a heart rate of 111 beats per minute.
Discussion
PRIS lacks a formal definition but has been described in studies as bradycardia accompanied by either metabolic acidosis, hepatitis/hepatomegaly, hyperlipidaemia or rhabdomyolysis; various other findings have been reported including lactate elevation, fevers, other bradyarrhythmias and tachyarrhythmias, acute kidney injury and hyperkalaemia.1 Classically, this syndrome has been described in the paediatric population, with the first ever recorded case being observed in a 2-year-old girl in 1990.2 Since then, several cases in adults have been reported. Risk factors include younger age group, high infusion rate (high dose) and prolonged duration of infusion.3
The underlying mechanism for PRIS is theorised to be secondary to lipid microembolisation caused by inactive propofol metabolites.4 Experiments have shown that propofol inhibits fatty acid metabolism, generating free fatty acids; propofol also inhibits coenzyme Q and cytochrome c, thus inhibiting the electron transport chain.5 Free fatty acids generated consequently are proarrhythmogenic. In addition, carbohydrate stores are rapidly depleted and can cause the observed multiorgan manifestations.6
The hallmark of PRIS is acute, refractory bradycardia. Also specific to this syndrome is a Brugada-like pattern seen on ECG; coved ST-segment elevations can be seen in the precordial leads V1–V3.7 Interestingly, an experimental study noted the relationship between higher doses of propofol (>10 µmol/L) and prolonged AV conduction interval, which is manifested further as sinoatrial interval and bradycardia.8 Atrial fibrillation is not typically associated with PRIS, however, a study from Cervigón et al demonstrates direct effect of propofol on the atria identified as increased organisation of electrical activity in the right atrium with the opposite effect seen in the left atrium.9 There have been cases documenting atrial fibrillation, polymorphic tachycardias, ventricular tachycardias and bundle branch blocks,10–12 however, there are no reports in literature of refractory atrial fibrillation with rapid ventricular response. Eventually, PRIS is thought to be fatal secondary to cardiovascular collapse or asystole.
The case outlined above is unique in that not only was the patient’s syndrome indicated by refractory atrial fibrillation with rapid ventricular response, but she was also noted to have a lipaemic blood draw which is observed rarely.13 14 Among targeted treatment options, we stopped the propofol infusion and specifically employed the use of an insulin-dextrose infusion in order to mitigate the damage from ATP depletion and free fatty acid generation. We noticed a direct improvement in the patient’s hypertriglyceridaemia and fevers with this intervention. The mortality rate with this syndrome remains very high, however, survivors in both the paediatric and adult populations have been reported.2 Given the high mortality rate, it is imperative that we increase recognition and minimise risk as much as possible.
Learning points
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Recognise the signs and symptoms that can indicate the start of propofol infusion syndrome, including refractory atrial fibrillation.
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Minimise using propofol infusions for extended durations, particularly in patients that are younger and have a higher body mass index.
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The use of insulin-dextrose infusions may help offset the underlying pathology.
Ethics statements
Patient consent for publication
Acknowledgments
Courtney Dearmond, RN—obtaining the lipemic blood draw sample and image attached above.
Footnotes
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Contributors MNS (conceptualisation; writing—original draft; writing—review and editing). EH (conceptualisation; writing—original draft). BX (conceptualisation; supervision)
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.
References
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