Propofol Is Mitochondrion-Toxic and May Unmask a Mitochondrial Disorder

Abstract

There are indications that preexisting mitochondrial disorders or beta-oxidation defects predispose for propofol infusion syndrome. This review aimed at investigating if propofol infusion syndrome occurs exclusively in patients with mitochondrial disorder and if propofol can unmask a mitochondrial disorder. Propofol infusion syndrome has been reported in genetically confirmed mitochondrial disorder patients. In addition, muscle biopsy of patients with propofol infusion syndrome revealed complex IV or complex II deficiency. In animal studies propofol disrupted the electron flow along the respiratory chain and decreased complex I, complex II, and complex III of the respiratory chain. In addition, propofol disrupted the permeability transition pore and reduced the mitochondrial membrane potential. In conclusion, propofol is mitochondrion-toxic and mitochondrial disorder patients should not receive propofol in high dosages over a prolonged period of time. Short-term application of propofol should be safe even in mitochondrial disorder patients. Not only does propofol infusion syndrome occur in mitochondrial disorder patients, but mitochondrial disorder patients are likely at higher risk to develop propofol infusion syndrome. Patients who develop propofol infusion syndrome should be screened for mitochondrial disorder. Propofol infusion syndrome is preventable if risk factors are thoroughly assessed, and if long-term propofol is avoided in patients at risk for propofol infusion syndrome.

Keywords

propofol mitochondrion toxicity side effects rhabdomyolysis myopathy mitochondrial disorder respiratory chain electron transport

Propofol has been repeatedly reported to cause muscular side effects. These include toxic myopathy^1,2 and rhabdomyolysis.³ Muscular side effects most frequently develop in association with the propofol infusion syndrome. Propofol infusion syndrome is defined as metabolic acidosis (lactic acidosis) with a base deficit >10 mmol/l at least at 1 occasion, arrhythmias, heart failure, renal insufficiency, hepatomegaly, and rhabdomyolysis following the infusion of propofol.^2,4,5 The mortality of propofol infusion syndrome is up to 50%.⁴ There are some indications that propofol infusion syndrome may be related to mitochondrial defects.^2,6 Whether propofol infusion syndrome develops particularly in patients with an underlying mitochondrial disorder, defined as a biochemically or genetically confirmed respiratory chain defect, or can unmask a mitochondrial disorder is unknown. Sedation and anesthesia alone carry an increased risk in mitochondrial disorder patients.⁶ Here the authors summarize and discuss recent and previous findings concerning the relation between propofol infusion syndrome and mitochondrial disorders. In particular, the authors address the question whether propofol infusion syndrome occurs exclusively in patients with manifest or subclinical mitochondrial disorder.

Methods

Data for this review were identified by searches of Medline, Current Contents, Embase, Web of Science, Web of Knowledge, LILACS, Scopus, and Google Scholar for references of relevant articles using the search terms “muscle,” “myopathy,” “rhabdomyolysis,” “mtDNA,” “respiratory chain,” and “neuromuscular,” in combination with “propofol” and “propofol infusion syndrome.” Randomized (blinded or open label) clinical trials, longitudinal studies, case series, and case reports were considered. Abstracts and reports from meetings were not included. Only articles published in English, French, Spanish, or German between 1966 and 2015 were included. Appropriate articles were studied and discussed for their usefulness to be incorporated in this review.

Results

Altogether, 47 articles about the effect of propofol on mitochondrial disorder patients respectively on mitochondria were identified. Twenty-eight of these articles reported mitochondrial disorder patients receiving propofol either for anesthesia or sedation on the intensive care unit (Table 1). These 28 articles reported 37 patients with a mitochondrial disorder who received propofol with or without side effects (Table 1). In 2 patients a mitochondrial disorder due to a mtDNA mutation was diagnosed.^2,7 Both of them died from propofol infusion syndrome or the mitochondrial disorder (Table 1). In 3 mitochondrial disorder patients maintenance with propofol caused short-lived bradycardia in 2 and cardiac arrest in 1 of them (Table 1). In 1 patient short-lived hyperthermia occurred after the fifth intravenous anesthesia with propofol (Table 1). At least 26 mitochondrial disorder patients were reported in whom induction of anesthesia with propofol or maintenance with propofol did not induce muscular or cardiac side effects (Table 1).

Table 1.

MID Patients Undergoing Anesthesia With Propofol in Which PIS, Other Propofol-Related Adverse Reactions, or No Side Effects Have Been Reported.

Age (y)	Sex	UMP	IN	MAI	DOPA	Dur	AR	Outcome	Reference	PT
27	f	POLG1	nm	yes	10.7 mg/kg/h	69 h	PIS	fatal	2	FP
40	m	ND1	no	yes	4.8 mg/kg/h	88 h	PIS	fatal	7	FP
1	m	COX ↓	no	yes	10.0 mg/kg/h	51 h	PIS	recovery	8	AB
2	f	COX ↓	yes	yes	6 mg/kg/h	5 h	PIS	recovery	10	FP
2	m	BOD	no	yes	5.2 mg/kg/h	72 h	PIS	recovery	9	FP
16	f	tRNA	yes	no	1.5 mg/kg	na	PIS	recovery	26	FP
nm	nm	KSS	nm	yes	nm	nm	Arrh.*	recovery	27	AB
nm	nm	KSS	nm	yes	nm	nm	Arrh.*	recovery	27	AB
50	f	CPEO	yes	yes	nm	nm	Arrh.^#	recovery	28	AB
6	m	LS	yes	yes	50-150 µg/kg/min	nm	none	recovery	14	FP
26	f	MNGIE	yes	yes	nm	nm	none	recovery	36	AB
49	f	EM	yes	yes	nm	nm	none	recovery	38	AB
40	m	KSS	yes	no	nm	na	none	recovery	39	FP
58	f	MELAS	nm	yes	nm	nm	none	recovery	40	AB
23	f	MELAS	yes	yes	2 µg/ml	nm	none	recovery	41	FP
11	m	C-III	yes	yes	nm	nm	none	recovery	42	AB
15	f	EM	yes	no	30 mg	na	none	recovery	43	AB
nm	nm	KSS	nm	yes	nm	nm	none	recovery	44	AB
nm	nm	EM	yes	yes	nm	nm	none	recovery	45	AB
57	f	EM	nm	yes	nm	nm	none	recovery	46	AB
6	m	MELAS	nm	yes	nm	nm	none	recovery	47	AB
27	f	KSS	yes	no	nm	na	none	recovery	48	AB
48	f	Luft dis.	yes	yes	nm	nm	HT	recovery	49	AB
49	f	NSMID	yes	yes	4-8 mg/kg/h	nm	none	recovery	12	AB
2	f	C-I, C-IV	yes	yes	35-100 µg/kg/min	nm	none	recovery	11	FP
6	f	C-I	nm	yes	nm	nm	none	recovery	13	AB
6 pat.	nm	nm	nm	yes	nm	nm	none	recovery	16	AB
5 pat.	3 f, 2 m	LS	yes	yes	50-100 µg/kg/min	nm	none	recovery	35,50	FP

Abbreviations: AB, abstract; AR, adverse reactions; Arrh., short-lived bradycardia after propofol + fentanyl respectively propofol + alfentanil; BOD, beta-oxidation defect; CPEO, progressive external ophthalmoplegia; DOPA, dosage of propofol applied; Dur, duration of propofol application; EM, encephalomyopathy; FP, full paper; h, hours; HT, hyperthermia one; IN, propofol for induction; KSS, Kearns-Sayre syndrome; LS, Leigh syndrome; MAI, propofol for maintenance; MELAS, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes; MID, mitochondrial disorder; MNGIE, myo-neuro-gastro-intestinal encephalopathy; na, not applicable; nm, not mentioned; NSMID, nonsyndromic MID; pat., patients; PIS, propofol infusion syndrome; PT, paper type; UMP, mutated gene, biochemical defect, or MID; y, years.

*Bradycardia.

^#Cardiac arrest.

Clinical Evidence for Mitochondrion-Toxicity of Propofol

Propofol infusion syndrome has been reported in at least 2 patients with a genetically confirmed mitochondrial disorder.^2,7 In 1 of these patients the mitochondrial disorder was detected after the occurrence of propofol infusion syndrome.⁷ The first patient was a 27-year-old female admitted for status epilepticus for which she received propofol since other antiepileptic agents were ineffective.² Shortly afterward she developed propofol infusion syndrome and a mitochondrial disorder was suspected, which was confirmed by detection of a POLG1 mutation. The patient died from intractable status epilepticus 68 days after admission.² Most likely this patient died from the underlying mitochondrial disorder since patients carrying POLG1 mutations frequently have a fatal outcome. The second patient was a blind 40-year-old male who experienced an epidural hematoma in the right frontoparietal region during an accident as a pedestrian necessitating urgent trepanation.⁷ After postoperative sedation with propofol during 88 hours he developed a propofol infusion syndrome and propofol was immediately stopped.⁷ Despite maximal supportive therapy, metabolic equilibrium could not be restored and the patient died 120 hours after admission.⁷ This patient more likely died from propofol infusion syndrome than the underlying mitochondrial disorder or traumatic brain injury. Postmortem genetic studies revealed the primary LHON mutation m.3460G>A.⁷ In a third patient, a child that developed propofol infusion syndrome after maintenance anesthesia with propofol, muscle biopsy after recovery from propofol infusion syndrome revealed reduced activity of complex IV of the respiratory chain.⁸ In a fourth patient, a 2-year-old boy experiencing propofol infusion syndrome, postanesthetic muscle biopsy revealed reduced activity of complex II of the respiratory chain and impaired uptake of acyl-carnitine due to CPT-I inhibition.⁹ In an 18-month-old female with multisystem disease, muscle biopsy after having experienced propofol infusion syndrome revealed cytochrome-c-oxidase deficiency (Table 1).¹⁰ In a 16-year-old female with MELAS syndrome sedation with propofol for carrying out a cerebral MRI resulted in severe acidosis, neurologic deterioration, and cardiopulmonary compromise (Table 1).

Evidence That Propofol Is Not Mitochondrion-Toxic

There are also reports showing that propofol does not induce muscular side effects in each patient with a mitochondrial disorder. In a child with 2 disorders, Prader-Willi syndrome and mitochondrial myopathy, anesthesia with ketamine fentanyl, rocuronium, caudal morphine, and a propofol infusion for open heart surgery was well tolerated (Table 1).¹¹ Absence of muscular side effects in this particular patient could be attributed to avoidance of continuous propofol infusion over >48 hours.¹¹ Another example for an uneventful propofol anesthesia in a mitochondrial disorder patient is a 49-year-old Japanese female with nonsyndromic mitochondrial disorder manifesting with muscle weakness, deafness, and dementia, who underwent general anesthesia with propofol (4-8 mg/kg/h) for implantation of an artificial cochlear device (Table 1).¹² The patient had a smooth recovery from propofol anesthesia and the bispectral index returned to preanesthetic levels within 10 minutes after completion of anesthesia.¹² Absence of side effects in this case could be attributed to the only short duration of anesthesia and application of low-dose propofol. In a 6-year-old girl with complex I deficiency anesthesia with a propofol infusion, caudal analgesia, and spontaneous ventilation for hip reconstruction after fracture, was tolerated without any side effects.¹³ Absence of side effects was most likely attributable to only short-term application of propofol and low dosages also in this patient.¹³ In a patient with Leigh-syndrome a single application of 20 mg propofol and maintenance dosage of 50-150 µg/kg/min did not cause any side effects (Table 1).¹⁴ A number of other mitochondrial disorder patients were reported who tolerated propofol anesthesia without major side effects (Table 1).

Absence of Propofol Infusion Syndrome in Nonmitochondrial Myopathies

In myopathy other than mitochondrial myopathy propofol was administered and well tolerated without the development of a propofol infusion syndrome.^15

-19 In a 56-year-old male with distal myopathy with rimmed vacuoles anesthesia with propofol, remifentanil, and ketamine for laparoscopic nephrectomy was smooth and well tolerated without inducing any side effects or propofol infusion syndrome.¹⁵ In patients with very long-chain acyl-coenzyme A dehydrogenase deficiency, a β-oxidation defect manifesting as hypoglycemia, liver disease, cardiomyopathy, and rhabdomyolysis, a literature search did not show that propofol is harmful to these patients if catabolism by adequate supply of carbohydrates is avoided.¹⁶ In a 43-year-old female with spinal muscular atrophy undergoing laparotomy for ovarian teratoma, general anesthesia with propofol did not cause any major side effects.¹⁷ In a 17-year-old male with Fukuyama congenital muscular dystrophy, general intravenous anesthesia with propofol and remifentanil for scoliosis repair, emergence, and recovery from anesthesia was rapid and muscle strength sufficient to extubate the patient just after surgery.¹⁸ In a patient with centronuclear (myotubular) myopathy, general anesthesia with propofol and remifentanil did not cause any muscular side effects.^19,20 In a patient with Duchenne muscular dystrophy undergoing posterior spinal fusion, general anesthesia with propofol and fentanyl for induction and maintenance did not induce any muscular adverse reactions or deterioration of the preanesthesia status.²¹ In a 42-year-old male with limb girdle muscular dystrophy who received a skin graft for a third degree burn, general anesthesia with propofol, fentanyl, vecuronium and nitrous oxide induced a Wenkebach AV-block-II but no other manifestations of a propofol infusion syndrome.²² The arrhythmias responded favorably to ephedrine, atropine, and reduction of the propofol infusion rate.²² Total intravenous anesthesia with propofol for open gastrostomy in a patient with Werdnig-Hoffmann disease was safe.²³ Several other patients with nonmitochondrial disorder neuromuscular disorder received propofol without major adverse reactions.

Discussion

Propofol is a liquid anesthetic used for sedation in mechanically ventilated patients or occasionally for status epilepticus. Propofol infusion syndrome is usually seen with infusion rates >5 mg/kg/h for >48 hours² but may occur at lower dosages as well (Table 1). Serum creatine-kinase can be markedly elevated. Electromyography in propofol infusion syndrome patients is reported to be myogenic.²⁴ Muscle biopsy may show necrotic fibers and loss of thick filaments.²⁴ Biochemical investigations of the muscle homogenate in propofol infusion syndrome patients may show decreased activity of complex IV or complex II.^8,9 Pathogenetically, propofol infusion syndrome is explained by inhibition of the uptake of free fatty acids into mitochondria.⁵ Another explanation for the development of propofol infusion syndrome is disruption of specific sites of the respiratory chain.^2,5 In addition, propofol interacts with the mitochondrial permeability transition pore resulting in decreased mitochondrial membrane potential and apoptosis.²⁵ Risk factors for the development of propofol infusion syndrome include young age, critical illness, acute neurological injury, low carbohydrate and high fat intake, catecholamine use, steroid administration, propofol use >48 hours, propofol dosage >4-5 mg/kg/h, preexisting β-oxidation defect, and preexisting mitochondrial disorder.² Treatment of propofol infusion syndrome is based on the immediate discontinuation of propofol and supportive therapy for acidosis, hyperkaliemia, renal failure, and rhabdomyolysis.²

There is some evidence that propofol is mitochondrion-toxic.² First, 2 genetically confirmed mitochondrial disorder patients have been reported in which propofol infusion syndrome occurred.^2,7 In 1 of these patients the mitochondrial disorder was detected only after the occurrence of propofol infusion syndrome.⁷ Second, in a child with propofol infusion syndrome reduced activity of complex IV of the respiratory chain was found on muscle biopsy after propofol infusion syndrome.⁸ Whether impaired respiratory chain activity was a direct toxic effect of anesthesia or indicative of a subclinical mitochondrial disorder remained questionable.⁸ Reduced complex IV deficiency was also reported in another patient with propofol infusion syndrome.¹⁰ Third, in a patient with propofol infusion syndrome uptake of acyl-carnitine was impaired due to inhibition of CPT1 and CPT2 and the activity of complex II of the respiratory chain was reduced.⁹ The patient was suspected to suffer from a β-oxidation defect.⁹ Fourth, in a child with MELAS-syndrome application of a single dose of propofol resulted in exacerbation of the mitochondrial disorder with severe acidosis, cardiorespiratory compromise, and neurological deterioration (Table 1).²⁶ Fifth, in 2 patients with Kearns-Sayre syndrome general anesthesia with propofol and fentanyl respectively propofol and alfentanil resulted in short-term sinus-bradycardia, which resolved after administration of atropine.²⁷ In an adult with progressive external ophthalmoplegia and lung cancer anesthesia with propofol resulted in ventricular fibrillation and cardiac arrest followed by successful resuscitation.²⁸ Sixth, in animal studies it has been shown that propofol disrupts the electron flow along the respiratory chain.^29,30 Seventh, in a recent study in rats propofol reduced the activity of complex II and complex III of the respiratory chain, an effect which increased with increasing dosages of propofol.³¹ The authors concluded that coenzyme-Q is the major site of propofol toxicity.³¹ Also in rats propofol inhibited the respiratory chain at the level of complex I.³² On the contrary, low concentrations of propofol did not damage isolated heart mitochondria.³³ In higher dosages, however, propofol reduced the mitochondrial membrane potential in liver mitochondria.²⁹ Whether propofol is exclusively or predominantly mitochondrion-toxic in patients carrying a mitochondrial defect is unknown but it can be speculated that in patients with a preexisting mitochondrial disorder propofol will further deteriorate mitochondrial functions.

Arguments against a clinically significant mitochondrion-toxic effect of propofol come from a review of 97 adult mitochondrial disorder patients who had undergone generalized anesthesia.³⁴ In none of those undergoing total intravenous anesthesia with propofol did propofol infusion syndrome occur.³⁴ Five patients with Leigh-syndrome undergoing insertion of a percutaneous endoscopic gastrostomy under sedation with low-dose propofol did not experience any side effects.³⁵ In a 26-year-old female with myo-neuro-gastro-intestinal encephalopathy maintenance of general anesthesia with propofol did not result in any muscular or nonmuscular side effects.³⁶ A number of other mitochondrial disorder patients have been reported in whom either induction or maintenance of anesthesia with propofol did not induce any adverse reactions (Table 1). Assuming that mitochondrial disorder patients are particularly at risk of developing propofol infusion syndrome,³⁷ it must be recommended to avoid propofol in high doses over a long time in mitochondrial disorder patients. Whether muscle-toxic comedication such as statins, steroids, colchicine, or cyclosporine predisposes for the development of propofol infusion syndrome is unknown but suspicion about a contributory effect of these agents has been raised.¹

Limitations of the review are that patients with propofol infusion syndrome have not been systematically investigated for mitochondrial disorder. Furthermore, mitochondrion-toxicity of propofol has not been systematically investigated in animal models of mitochondrial disorders. There are also no systematic studies about the propofol effect in cell cultures derived from mitochondrial disorder patients available. A further limitation is that the diagnosis mitochondrial disorder was genetically confirmed in only 2 of 37 patients included in this review and that the diagnosis relied on biochemical or immune-histological investigations in the remaining cases. The review is also limited by the probability that mitochondrial disorders with an increased risk of propofol infusion syndrome are far more likely to get reported than mitochondrial disorder patients who do not develop propofol infusion syndrome during anesthesia. Thus, the true number of patients who receive propofol but do not get propofol infusion syndrome is unknown. Last, some articles were available only as an abstract because they were written in Japanese or were inaccessible.

It is concluded that, based on available medical literature, mitochondrial disorder patients are likely at higher risk to develop propofol infusion syndrome but the underlying pathophysiology is not fully understood. Mitochondrial disorder patients should not receive propofol for a prolonged period of time. Short-term application of propofol, even in high dosages, should be safe even in mitochondrial disorder patients. Patients who develop propofol infusion syndrome should be screened for mitochondrial disorder. Propofol infusion syndrome may be life-threatening but it is preventable if risk factors are thoroughly assessed, and if propofol is avoided over a prolonged period of time in patients at risk of developing propofol infusion syndrome.

Footnotes

Author Contributions

JF and MF contributed equally.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical Approval

All ethical standards required were accomplished.

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