Propofol & SZ...

[Ace844]

Nate,

Other than the info posted here above. I have heard and there is a "Study," I posted here on the 'board' (I'll try to find the link and post it) which covers cases where pt's who have been on a Diprovan drip have suffered irreversable cardiac arrest inducing acidosis...perhaps one of the variations of symptomatology you are see with this may be seizure activity?

Hope this helps,

ACE844

[Ace844]

Nate,

Other than the info posted here above. I have heard and there is a "Study," I posted here on the 'board' (I'll try to find the link and post it) which covers cases where pt's who have been on a Diprovan drip have suffered irreversable cardiac arrest inducing acidosis...perhaps one of the variations of symptomatology you are see with this may be seizure activity?

Hope this helps,

ACE844

(Anesthesiology: Volume 101(1) July 2004 pp 239-241

Metabolic Acidosis Associated with Propofol in the Absence of Other Causative Factors

Burow @ Bethanie K. M.D.*; Johnson, Michael E. M.D., Ph.D.†; Packer, Douglas L. M.D.‡

* Resident, Transitional Year, Gundersen Lutheran Medical Center, LaCrosse, Wisconsin. † Assistant Professor of Anesthesiology, ‡ Professor of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota.

This article is accompanied by an Editorial View. Please see: Funston JS, Prough DS: Two reports of propofol anesthesia associated with metabolic acidosis in adults. Anesthesiology 2004; 101:6-8.

Received from the Anesthesiology Department, Mayo Clinic College of Medicine.

Submitted for publication October 15, 2003.

Accepted for publication February 3, 2004.

Supported by the Mayo Foundation, Rochester, Minnesota.

Presented in preliminary form at the Midwest Anesthesia Residents Conference, Omaha, Nebraska, March 10, 2002; the Third International Interdisciplinary Congress EuroNeuro 2002, Munich, Germany, September 12-14, 2002; and the 30th Annual Meeting of the Society of Neurosurgical Anesthesia and Critical Care, Orlando, Florida, October 11, 2002.

Address correspondence to Dr. Johnson: Mayo Clinic Anesthesiology SMH 2-MB, 200 Southwest First Street, Rochester, Minnesota 55905. Address electronic mail to: johnson.michael@mayo.edu. Individual article reprints may be purchased through the Journal Web site, www.anesthesiology.org)

Metabolic Acidosis Associated with Propofol in the Absence of Other Causative Factors

Burow, Bethanie K. M.D.*; Johnson, Michael E. M.D., Ph.D.†; Packer, Douglas L. M.D.‡

* Resident, Transitional Year, Gundersen Lutheran Medical Center, LaCrosse, Wisconsin. † Assistant Professor of Anesthesiology, ‡ Professor of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota.

This article is accompanied by an Editorial View. Please see: Funston JS, Prough DS: Two reports of propofol anesthesia associated with metabolic acidosis in adults. Anesthesiology 2004; 101:6-8.

Received from the Anesthesiology Department, Mayo Clinic College of Medicine.

Submitted for publication October 15, 2003.

Accepted for publication February 3, 2004.

Supported by the Mayo Foundation, Rochester, Minnesota.

Presented in preliminary form at the Midwest Anesthesia Residents Conference, Omaha, Nebraska, March 10, 2002; the Third International Interdisciplinary Congress EuroNeuro 2002, Munich, Germany, September 12-14, 2002; and the 30th Annual Meeting of the Society of Neurosurgical Anesthesia and Critical Care, Orlando, Florida, October 11, 2002.

Address correspondence to Dr. Johnson: Mayo Clinic Anesthesiology SMH 2-MB, 200 Southwest First Street, Rochester, Minnesota 55905. Address electronic mail to: johnson.michael@mayo.edu. Individual article reprints may be purchased through the Journal Web site, www.anesthesiology.org .

PROPOFOL is commonly used for intensive care unit sedation and prolonged procedures in the adult population where both deep sedation and quick emergence are required. Several recent reports have described a propofol infusion syndrome, occurring in both pediatric1-7 and adult2,8-10 patients receiving prolonged high-dose infusions of propofol (> 75 μg · kg-1 · min-1 × > 24 h). The syndrome is characterized as a severe metabolic acidosis, sometimes associated with myocardial dysfunction, rhabdomyolysis, or death. Although some reports have documented high anion gap, lactic acidosis, others have documented only a metabolic acidosis without further characterization. All cases of propofol infusion syndrome reported thus far have occurred in critically ill patients receiving multiple other drugs, creating some controversy as to whether propofol alone was its cause.11-13 We now report a case of metabolic acidosis, without ventilatory depression or hypoxia, in an otherwise healthy patient receiving propofol as the sole anesthetic agent during an ablation for atrial fibrillation. Approval for this case review was obtained from the institutional review board of the Mayo Clinic College of Medicine.

Case Report

A 31-yr-old woman (weight, 99.2 kg; height, 162 cm) with chronic atrial fibrillation was scheduled to undergo radiofrequency ablation for pulmonary vein isolation. She had a history of atrial fibrillation since the age of 22 yr and was minimally symptomatic, with no evidence of rate-related ventricular dysfunction or thromboembolic events. Except for occasional gastric reflux, she was otherwise healthy. She had reported waking up early during a previous anesthetic. Echocardiography showed normal ventricular function with a left ventricular ejection fraction of 55% and mild atrial enlargement. Medications were limited to 50 mg atenolol daily (stopped 4 days before ablation), 325 mg aspirin daily, and oral contraceptives. Preoperative laboratory results were unremarkable, including 11.5 g/dl hemoglobin, 0.9 mg/dl creatinine, 138 mEq/l Na+, and 4.9 mEq/l K+.

The initial anesthetic plan was to use propofol as the sole sedative, based on its rapid metabolism and the clinical impression that propofol suppresses arrhythmogenic foci during radiofrequency ablation to a lesser extent than other available anesthetic agents. Monitoring included electrocardiography, pulse oximetry, continuous carbon dioxide monitoring of gas sampled at the nares, a femoral arterial catheter, and a urinary catheter. Because of the potential for respiratory depression with prolonged deep sedation in a nonintubated patient, arterial blood gas analyses were obtained intermittently during the procedure.

Sedation was induced with 25 μg · kg-1 · min-1 propofol with supplemental oxygen by facemask at 4 l/min. The Diprivan® Injectable Emulsion formulation of propofol (AstraZeneca, Wilmington, DE) was used throughout, containing 10 mg/ml propofol and 0.005% disodium edetate. The exact vial sizes used were not recorded on the written anesthesia record. Based on our practice patterns at that time, the propofol infusion was almost certainly administered directly from a 100-ml infusion vial sterilely spiked with a solution administration set leading to an infusion pump. The source of supplemental boluses was not specified on the written record but would have been either from the 100-ml infusion vial already in use or from a 20-ml glass vial opened separately. Our practice is to discard unused propofol at the end of each case, so that vials would have been opened fresh for this case. The case reported was the first case of the day, and vials would have been open no longer than 1 h before the case. Lot numbers and expiration dates for the vials of propofol used could not be identified on retrospective inspection.

The rate of propofol infusion was quickly increased to assist with patient immobility and ranged from 50 to 125 μg · kg-1 · min-1 throughout the procedure, together with intermittent boluses. The course of propofol therapy and arterial blood gases during the procedure is shown in figure 1. The average rate at which propofol was administered was 83 μg · kg-1 · min-1, over a period of 395 min. An acidosis progressively developed, which was entirely metabolic. Pulse oximetry documented oxygen saturation (Spo2) greater than 95% at all times, and arterial oxygen tension (Pao2) and arterial carbon dioxide tension (Paco2) showed no evidence of hypoxia or respiratory depression on any arterial blood gas. There was no prolonged hypotension, and the average urine output was 250 ml/h throughout the procedure. Blood loss was minimal. The only other drug therapies used while propofol was administered were heparin, cefazolin, and 2 mg midazolam given as 1 mg at 51 min and 2 × 0.5 mg at 180 min after the start of anesthesia. Na+ and K+ at 51 and 194 min were 142 and 4.2 mEq/l and 142 and 4.0 mEq/l, respectively.

Fig. 1. Propofol administration and changes in arterial blood gas values in subject of case report. Propofol was stopped at 395 min, and the patient was intubated and mechanically ventilated at 400 min. Note subsequent improvement in pH, bicarbonate (HCO3-), and base excess beyond that predicted by mild decrease in partial pressure of carbon dioxide (Pco2). Note also partial pressure of oxygen (Po2) greater than 100 mmHg during propofol administration. The increased Po2 at 289 min was due to supplemental mask oxygen administered during manual correction of transient airway obstruction.

At 395 min, the pH was 7.30, and base excess was -8. Because of patient restlessness and movement despite heavy sedation, intermittent airway obstruction requiring manual positioning to correct, and concern about an evolving metabolic acidosis with high-dose propofol, the patient was intubated and mechanically ventilated. The propofol infusion was discontinued, and no further propofol boluses were given. Total intravenous fluid to this point was between 2 and 3 l saline, 0.9%. A fentanyl infusion at 17-34 ng · kg-1 · min-1 with 75% N2O was begun and continued for the rest of the procedure. Sodium bicarbonate 15 mEq was given at 475 min, but the largest change in pH and base excess toward normal occurred between discontinuation of propofol at 395 min and the blood gas sampled at 433 min. By 560 min, the metabolic acidosis had partially resolved. At the end of the procedure at 720 min, the trachea was extubated without complications. Total intravenous fluid during the procedure was 5.85 l saline, 0.9%. No further arterial blood gas analyses were obtained on the day of the procedure. After the procedure, the patient had normal physical examination results and no complaints. Laboratory values obtained 2-4 days after the procedure were unremarkable: Na+, 137-139 mEq/l; K+, 3.5-3.9 mEq/l; Cl- 103-106 mEq/l; venous HCO3 - 25-26 mEq/l; anion gap, 8.

Discussion

We report the development of significant, reversible, metabolic acidosis without ventilatory depression or hypoxia in a healthy patient receiving high-dose propofol and no other drugs likely to cause metabolic acidosis. The mechanism for this mild probable propofol infusion syndrome remains unclear. There was no evidence of renal failure causing decreased excretion of endogenous acids or increased loss of bicarbonate. Moreover, venous bicarbonate, creatinine, and anion gap values obtained after the procedure were normal, showing the absence of underlying chronic renal disease.

Increased lactic acid production caused by low cardiac output or a regional steal syndrome must be considered because propofol is both a cardiac depressant and vasoactive,14 and cardiac failure has been reported with the propofol infusion syndrome.1,2 However, cardiac failure with propofol is usually a late, fatal development after metabolic acidosis, rather than an early cause of metabolic acidosis. This patient's hemodynamics, urine output, and stable renal status argue against cardiovascular failure as the proximate cause of her metabolic acidosis.

Another potential cause of this patient's metabolic acidosis is impaired hepatic lactate metabolism. In several cases of propofol infusion syndrome, the development of a fatty or enlarged liver has been reported, and a case of isolated severe hepatotoxicity associated with propofol has also been reported.15 The patient reported here did not have liver function laboratory tests, but she had no clinical evidence of hepatic disease before or after the procedure.

There is both in vitro 16 and clinical7 evidence that high doses of propofol can inhibit mitochondrial respiration, which could cause metabolic acidosis. The glucuronide and sulfate products of phase II propofol metabolism are unlikely to be toxic, but the intermediate dihydroxylated products are poorly characterized and potentially interconvertible to toxic quinones. Propofol quinone has been synthesized, and preliminary evidence has been presented of its mitochondrial toxicity.17 Both a direct and a metabolite mitochondrial toxicity of propofol would be consistent with the idiosyncratic appearance of the propofol infusion syndrome, requiring both a sustained, high-dose infusion and as yet undetermined genetic variants of propofol clearance and metabolism.

Sepsis can lead to metabolic acidosis and could occur with contaminated propofol because its lipid emulsion is a good culture medium.18 Here, the lack of fever and sustained hypotension and the uneventful postoperative recovery argue against sepsis in this patient. No exogenous acid load was administered to this patient; she received only the Diprivan® formulation of propofol (pH 7.5-8.0), rather than a generic formulation (pH 4.5-6.4; Baxter Healthcare Corporation, New Providence, NJ).

Rapid administration of large volumes of 0.9% intravenous saline can cause dilutional acidosis.19,20 Unfortunately, the concentration of serum chloride, which would have clarified the contribution of saline administration to this patient's acidosis, was not determined during the acidosis. However, comparison to published studies of dilutional acidosis suggests that 0.9% saline is unlikely to account for all of this patient's acidosis. In adult gynecologic surgery patients receiving 6 l saline, 0.9%, over 2 h, base excess decreased to -6.7 mm by 2 h.20 Such dilutional changes require rapid administration of volumes beyond the ability of native homeostatic mechanisms to compensate.19 At the time of intubation, our patient had received at most 3 l saline, 0.9%, over 6.5 h, with a base excess of -8. Hence, compared with that study,20 our patient had a more negative base excess despite receiving half the saline volume over more than triple the time period, with more time for urinary response to a putative dilutional acidosis. Furthermore, her acidosis improved after the propofol was stopped, although she received a similar volume (at least 2.85 l) of 0.9% saline over the final 5.5 h of the anesthetic.

In conclusion, the case reported here is significant because it is the first documented example of propofol potentially causing metabolic acidosis in the absence of any other drug likely to cause acidosis and without any other reasonable causative factors. It suggests that propofol infusion syndrome is in fact due to propofol or a propofol metabolite, is reversible in its early stages, and is consistent with previous cautions to avoid high-dose, prolonged infusions of propofol.1,2 It also illustrates the utility of monitoring arterial blood gases in cases where the advantages of propofol infusion greater than 75 μg · kg-1 · min-1 for more than a few hours seem to outweigh its risks.

References

1. Bray RJ: Propofol infusion syndrome in children. Paediatr Anaesth 1998; 8:491-9

[CrossRef] [Context Link]

2. Cremer OL, Moons KG, Bouman EA, Kruijswijk JE, de Smet AM, Kalkman CJ: Long-term propofol infusion and cardiac failure in adult head-injured patients. Lancet 2001; 357:117-8

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3. Cray SH, Robinson BH, Cox PN: Lactic acidemia and bradyarrhythmia in a child sedated with propofol. Crit Care Med 1998; 26:2087-92

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4. Hanna JP, Ramundo ML: Rhabdomyolysis and hypoxia associated with prolonged propofol infusion in children. Neurology 1998; 50:301-3

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5. Hatch DJ: Propofol-infusion syndrome in children. Lancet 1999; 353:1117-8

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6. Kelly DF: Propofol-infusion syndrome. J Neurosurg 2001; 95:925-6

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7. Wolf A, Weir P, Segar P, Stone J, Shield J: Impaired fatty acid oxidation in propofol infusion syndrome. Lancet 2001; 357:606-7

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8. Perrier ND, Baerga-Varela Y, Murray MJ: Death related to propofol use in an adult patient. Crit Care Med 2000; 28:3071-4

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9. Stelow EB: Propofol-associated rhabdomyolysis with cardiac involvement in adults: Chemical and anatomic findings. Clin Chem 2000; 46:577-81

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10. Badr AE, Mychaskiw G, II, Eichhorn JH: Metabolic acidosis associated with a new formulation of propofol. Anesthesiology 2001; 94:536-8

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11. Nimmo GR, Mackenzie SJ, Grant IS: Haemodynamic and oxygen transport effects of propofol infusion in critically ill adults. Anaesthesia 1994; 49:485-9

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12. Kelly DF, Goodale DB, Williams J, Herr DL, Chappell ET, Rosner MJ, Jacobson J, Levy ML, Croce MA, Maniker AH, Fulda GJ, Lovett JV, Mohan O, Narayan RK: Propofol in the treatment of moderate and severe head injury: A randomized, prospective double-blinded pilot trial. J Neurosurg 1999; 90:1042-52

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13. Reed MD, Blumer JL: Propofol bashing: The time to stop is now! Crit Care Med 1996; 24:175-6

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14. Ririe DG, Lundell JC, Neville MJ: Direct effects of propofol on myocardial and vascular tissue from mature and immature rats. J Cardiothorac Vasc Anesth 2001; 15:745-9

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15. Anand K, Ramsay MA, Crippin JS: Hepatocellular injury following the administration of propofol. Anesthesiology 2001; 95:1523-4

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16. Schenkman KA, Yan S: Propofol impairment of mitochondrial respiration in isolated perfused guinea pig hearts determined by reflectance spectroscopy. Crit Care Med 2000; 28:172-7

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17. Johnson ME, Fauq AH, Uhl CB: Effect of propofol and propofol quinone on hydroxyl radical generation (abstract). Free Radic Biol Med 2002; 33(suppl 1):S202

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18. Bennett SN, McNeil MM, Bland LA, Arduino MJ, Villarino ME, Perrotta DM, Burwen DR, Welbel SF, Pegues DA, Stroud L, Zeitz PS, Jarvis WR: Postoperative infections traced to contamination of an intravenous anesthetic, propofol. N Engl J Med 1995; 333:147-54

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19. Prough DS, White RT: Acidosis associated with perioperative saline administration: Dilution or delusion? Anesthesiology 2000; 93:1167-9

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20. Scheingraber S, Rehm M, Sehmisch C, Finsterer U: Rapid saline infusion produces hyperchloremic acidosis in patients undergoing gynecologic surgery. Anesthesiology 1999; 90:1265-70

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© 2004 American Society of Anesthesiologists, Inc.

(Michael E. Johnson @ M.D., Ph.D.

Mayo Clinic College of Medicine, Rochester, Minnesota. johnson.michael@mayo.edu; Anesthesiology: Volume 102(3) March 2005 p 698; [

Metabolic Acidosis due to Propofol Infusion (Accepted for publication November 19, 2004.)]

Anesthesiology: Volume 102(3) March 2005 p 698

Metabolic Acidosis due to Propofol Infusion

Johnson, Michael E. M.D., Ph.D.

Mayo Clinic College of Medicine, Rochester, Minnesota. johnson.michael@mayo.edu

(Accepted for publication November 19, 2004.)

In Reply:-

I appreciate the interest of Dr. Farag et al. in the recent case report of asymptomatic metabolic acidosis in a patient receiving prolonged propofol infusion in the absence of any likely cause of the acidosis except propofol.1 I agree that an occult mitochondrial disease is a possible etiology. The anecdotal reports of Dr. Farag et al. on the effects of propofol in patients with mitochondrial disease are interesting, and I encourage them to publish details in a more systematized form.

However, their letter makes unsupported assumptions about propofol infusion syndrome that might adversely affect the level of vigilance for and detection of this complication. It is not true that hundreds of thousands of adult patients have received propofol without experiencing this complication. To the best of my knowledge, no large-scale study of acid-base balance on thousands of patients receiving high-dose, prolonged propofol infusion has been reported. The subject of the case report by me and my colleagues was completely asymptomatic and was detected only because concern about respiratory depression under deep sedation caused arterial blood gases to be checked.1 It is possible that mild forms of propofol-induced acidosis are much more common than appreciated, and it is also possible that they are as rare as suggested by Farag et al. We simply do not have the data at this time. A large-scale study is needed to answer the question.

It is also important to note that propofol infusion syndrome is so far defined only clinically, with metabolic acidosis being the invariant common factor, usually accompanied by circulatory collapse.1 Although propofol can have adverse effects on mitochondria in vitro,2 there are multiple potential pathways to the clinically defined syndrome besides mitochondrial disease. Pharmacogenomic variability in propofol metabolism and nonmitochondrial sites of propofol action could cause accumulation of propofol or unusual propofol metabolites,3,4 or loss of the cytoprotective effects of propofol,5-8 which might otherwise mask harmful effects of propofol. The recommendations of Farag et al. for anesthetizing patients with mitochondrial disease are reasonable and appropriate. However, anesthesiologists should still be vigilant for propofol infusion syndrome in patients without mitochondrial disease.

Michael E. Johnson, M.D., Ph.D.

Mayo Clinic College of Medicine, Rochester, Minnesota. johnson.michael@mayo.edu

References

1. Burow BK, Johnson ME, Packer DL: Metabolic acidosis associated with propofol in the absence of other causative factors. Anesthesiology 2004; 101:239-41

[Fulltext Link] [CrossRef] [Context Link]

2. Schenkman KA, Yan S: Propofol impairment of mitochondrial respiration in isolated perfused guinea pig hearts determined by reflectance spectroscopy. Crit Care Med 2000; 28:172-7

[Fulltext Link] [CrossRef] [Context Link]

3. Stevanato R, Momo F, Marian M, Rigobello MP, Bindoli A, Bragadin M, Vincenti E, Scutari G: Effects of nitrosopropofol on mitochondrial energy-converting system. Biochem Pharmacol 2002; 64:1133-8

[CrossRef] [Context Link]

4. Johnson ME, Fauq AH, Uhl CB: Effect of propofol and propofol quinone on hydroxyl radical generation (abstract). Free Radic Biol Med 2002; 33(suppl 1):S202

[Context Link]

5. Kahraman S, Kilinc K, Dal D, Erdem K: Propofol attenuates formation of lipid peroxides in tourniquet-induced ischaemia-reperfusion injury. Br J Anaesth 1997; 78:279-81

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6. Navapurkar VU, Skepper JN, Jones JG, Menon DK: Propofol preserves the viability of isolated rat hepatocyte suspensions under an oxidant stress. Anesth Analg 1998; 87:1152-7

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7. Mathur S, Farhangkhgoee P, Karmazyn M: Cardioprotective effects of propofol and sevoflurane in ischemic and reperfused rat hearts: Role of KATP channels and interaction with the sodium-hydrogen exchange inhibitor HOE 642 (cariporide). Anesthesiology 1999; 91:1349-60

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8. Gelb AW, Bayona NA, Wilson JX, Cechetto DF: Propofol anesthesia compared to awake reduces infarct size in rats. Anesthesiology 2002; 96:1183-90

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(Anesth Analg 2005;100:1468-1469

© 2005 International Anesthesia Research Society

doi: 10.1213/01.ANE.0000151717.74547.23

--------------------------------------------------------------------------------

NEUROSURGICAL ANESTHESIA

Severe Seizures During Propofol Induction in a Patient with Syringomyelia Receiving Baclofen

Sethuraman Manikandan @ MD, PDCC, Prabhat K. Sinha, MD, PDCC, Praveen K. Neema, MD, PDCC, and Ramesh C. Rathod, DA, MD

Department of Anesthesiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala

Address correspondence and reprint requests to S. Manikandan, MD, Assistant Professor, Department of Anesthesiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum-695011, Kerala, India. Address e-mail to kanmanis@sctimst.ac.in.)

We report the occurrence of recurrent severe generalized seizures during induction of anesthesia with propofol in a patient with syringomyelia receiving baclofen for flexor spasms undergoing neurosurgery. We discuss the possible epileptogenic interaction between baclofen and propofol in our patient

[web:9af4303409]http://www.diprivan.com/[/web:9af4303409]