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Anesthesia & Analgesia:
doi: 10.1213/ANE.0b013e318292cbd0
Anesthetic Pharmacology: Case Report

Profound Hypotension After Anesthetic Induction with Propofol in Patients Treated with Rifampin

Mirzakhani, Hooman MD*; Nozari, Ala MD, PhD; Ehrenfeld, Jesse M. MD, MPH; Peterfreund, Robert MD, PhD; Szabo, Michele MD; Walsh, John L. MD; Jiang, Yandong MD, PhD; Sandberg, Warren MD, PhD; Rosow, Carl MD, PhD; Wang, Jingping MD, PhD

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From the *Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Broad Institute of MIT and Harvard; Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee.

Accepted for publication March 6, 2013

Published ahead of print May 17, 2013

Funding: Departmental.

The authors declare no conflicts of interest.

Drs. Hooman Mirzakhani and Ala Nozari contributed equally to the preparation of the manuscript.

Reprints will not be available from the authors.

Address correspondence to Ala Nozari, MD, PhD, Department of Anesthesia and Critical Care, Massachusetts General Hospital, GRJ-4–416, 55 Fruit St., Boston, MA 02114-2696. Address e-mail to anozari@partners.org.

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Abstract

Rifampin is commonly used for the treatment of tuberculosis and staphylococcal infections, as well as for prevention of infection in cardiac valve and bone surgeries. We report a case of profound hypotension after anesthesia induction with propofol in a patient who was treated with two 600 mg doses of rifampin for prophylaxis of infection before surgery. In a retrospective case-control study of 75 patients, we confirmed this potentially serious drug–drug interaction. After rifampin, there was a significant and prolonged arterial blood pressure reduction when patients received propofol, but not thiopental.

Rifampin is a synthetic derivative of rifamycin B that inhibits bacterial RNA polymerase by forming a stable drug-enzyme complex.1 It remains one of the most effective antimicrobials used in the treatment of tuberculosis,2 but it is also used to treat methicillin-resistant as well as methicillin-sensitive staphylococcal infections,3 or for prevention of infection in cardiac valve and bone surgeries.4–6 Here, we report a case of profound hypotension after anesthesia induction with propofol in a patient who was treated with rifampin. We examined this potentially important drug interaction with a retrospective case-control study of 75 patients.

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CASE REPORT

A 64-year-old woman (weight 88 kg, height 163 cm, body mass index 33) presented to our institution for an elective posterior decompression of a herniated disk at the L5-S1 level. She had a medical history significant for lumbar stenosis, symptomatic gastroesophageal reflux disease, hyperlipidemia, osteoporosis, and panic attacks. Her medications were atorvastatin (10 mg/d), esomeprazole (40 mg/d), and naproxen (1000 mg/d). She also took acetaminophen plus hydrocodone (5–325 mg), as needed for pain, and occasional multivitamins. The neurosurgical team prescribed rifampin 600 mg per os to be given the night before and 2 hours before surgery as prophylaxis for infection. The patient had no known allergies and described herself as physically active. She had a stress test performed 3 years previously which showed normal exercise tolerance and no evidence of myocardial ischemia. The patient remained nil per os for 7 hours after midnight, but she had normal intake of food and fluids before that. She was anxious, and her preinduction heart rate was 102 beats/min, and arterial blood pressure was 150/90 mm Hg. She received 2 mg midazolam and 150 µg fentanyl (1.88 µg/kg) IV. This moderately large premedication caused a decrease in anxiety but minimal respiratory and hemodynamic effects. At 7 minutes after fentanyl administration, rapid sequence induction was conducted using 200 mg propofol (2.3 mg/kg) and 100 mg succinylcholine (1.1 mg/kg), and a 7.0 mm endotracheal tube was inserted without difficulty. Three minutes after induction of anesthesia and before placing the patient in the prone position, her arterial blood pressure decreased to 60/30 mm Hg, and heart rate increased to 112 beats/min (Fig. 1). There was no wheezing or difficulty ventilating and no changes in skin color suggestive of an allergic reaction. Rapid IV infusion of normal saline was initiated (800 mL/20 min) in addition to phenylephrine infusion (10 µg/min) with incremental bolus doses, as needed. Ten milligrams of ephedrine (two 5 mg doses) and an 80 µg phenylephrine bolus were administered. Despite continued infusion of fluid, phenylephrine and ephedrine, her systolic blood pressure remained 60 to 70 mm Hg, although all central and peripheral pulses were palpable. Epinephrine was added in 0.04 mg bolus doses in addition to 80 µg doses of phenylephrine. After administering 2 doses of epinephrine (0.08 mg) and 3 more doses of phenylephrine (240 µg) the patient’s blood pressure finally improved to 92/53 mm Hg. Serial electrocardiogram showed no signs of ischemia or dysrhythmia during the hypotensive period or afterwards. She remained stable without additional epinephrine, although phenylephrine infusion was required to maintain her systolic blood pressure within 70% of her baseline (90–100 mm Hg). After some discussion, it was decided to proceed with the surgery with addition of normal saline infusion (1 L/h) to her continuous phenylephrine infusion. Approximately 35 minutes after induction, the patient was turned prone without hypotension, and surgery was completed without incident. The patient emerged from anesthesia and was tracheally extubated without problems. Her postoperative period was uneventful, and she was discharged to her home on postoperative day 3 with a satisfactory outcome.

Figure 1
Figure 1
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RETROSPECTIVE DATA

Rifampin is not frequently administered for infection prophylaxis, but it had been used this way for several years by members of our neurosurgical division doing spinal surgery. There had been anecdotal descriptions of similar hypotensive episodes by the neuroanesthesiologists in our department, and a connection with rifampin had been raised as a possibility. After the present dramatic episode occurred, we felt it was important to investigate our anesthesia and medical record database with the aim of identifying a potential new drug–drug interaction.

After IRB approval, which waived patient consent, we reviewed 194 anesthesia records and medical charts of patients who had undergone spine surgery under general anesthesia between 2008 and 2010 in our institution. We randomly selected 25 patients for each of 3 groups who were matched for type of surgery and surgeon:

1. Patients receiving propofol for induction of anesthesia and preoperative rifampin prophylaxis (experimental group);

2. Patients receiving propofol for induction but no rifampin pretreatment (propofol control); and

3. Patients receiving thiopental for induction and preoperative rifampin (thiopental control).

Our prospective power analysis indicated that group sizes of 25 would have 90% power to detect a 10 mm Hg difference in mean arterial blood pressure (MAP) reduction at a significance level of 0.05 (2-sided comparison), assuming a standard deviation of 10 mm Hg.7,8 The prophylactic dose of rifampin was uniformly 600 mg per os, the night before and on the morning of surgery (usually about 2 hours before) in both the propofol and thiopental groups. Patient characteristics (sex, age, height, weight, ASA physical status classification, Charlson Comorbidity Index [CCI]),9 first and total dose of IV anesthetics, total doses of vasopressors, fentanyl dose, and volume of administered fluids were recorded. Baseline (time of induction) and postinduction values of systolic, diastolic blood pressure, and MAP were obtained from the electronic anesthesia record system.

Differences between the groups in sex, age, weight, ASA, and CCI were examined by analysis of variance (ANOVA) for continuous variables and Kruskal–Wallis ANOVA for quantal variables. MAP responses were compared by 2-way ANOVA for repeated measures. Our dependent variable, change in MAP, was normally distributed for the 3 groups as assessed by the Shapiro–Wilk test. There was homogeneity of variance among groups as assessed by Levene test for equality of error variances. The change in MAP with time was analyzed for each of the study groups using a general linear univariate model to account for the impact of age, type and dose of anesthetic drug, fentanyl dose before induction, ASA status, CCI, presence of diabetes and hypertension, weight, location of surgery (cervical versus lumbar), vasopressor doses, and amount of fluid administered.

The significant covariates (duration of hypotension, fluid amount, anesthetic drug, presence or absence of rifampin) were examined in a general linear multivariate model. In the multivariate analysis, anesthetic drug was an independent predictor of hypotension (P < 0.001).

The induction dose of propofol did not differ among the groups. Patients’ baseline characteristics (Table 1) did not significantly influence nadir MAP. We did not find any association between preexisting hypertension and hypotensive events using χ2 and binary logistic regression (P = 0.564). Patients receiving rifampin and propofol had a significantly greater reduction in their MAP and duration of hypotension than propofol alone or thiopental with rifampin (Table 2) despite the fact that they received lower doses of fentanyl for induction (250 ± 65 µg) (Table 1). A post hoc test (Tukey Honestly Significant Difference) also showed a significant difference in nadir MAP (P = 0.004) and reduction of MAP (P < 0.001) in patients given rifampin and propofol versus propofol alone or thiopental–rifampin. The dose of phenylephrine was not normally distributed, and the Kruskal–Wallis ANOVA showed a significantly larger dose of phenylephrine in the propofol–rifampin group versus our control groups (P = 0.039, Table 2).

Table 1
Table 1
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Table 2
Table 2
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DISCUSSION

This case report and the retrospective data analysis demonstrated that the risk of a prolonged hypotensive episode increased almost 3-fold when propofol rather than thiopental was used for anesthetic induction in patients who received rifampin. In 10 of 25 cases, this exaggerated hemodynamic response required vigorous treatment with vasopressors and fluids, i.e., hypotension persisted despite >2 L Ringer’s lactate solution (or normal saline) as well as repeated doses of vasopressors. The peak hypotension might actually have been underestimated, since these patients did not have continuous measurements with an arterial line.

In our retrospective data analysis, neither did the duration of fluid abstinence differ among the groups,10 nor did the dose or type of preinduction anxiolytic drug (midazolam). The induction dose of propofol was similar with or without rifampin, and the fentanyl dose was lower in the propofol–rifampin group. However, the hemodynamic response was significantly greater in the propofol–rifampin group, suggesting a drug–drug interaction as the cause. Hemodynamic instability was not seen when rifampin was given with thiopental, indicating that the interaction is unique to propofol.

The mechanism for this interaction was not investigated. IV administration of rifampin alone can induce hypotension by a direct, dose-dependent reduction of vascular tone and systemic vascular resistance,11 and propofol-induced hypotension is largely due to venodilation.12 However, it is not clear whether oral administration of rifampin will do the same and whether any such effect would be relevant for propofol administration so many hours after the first and second doses.

Anaphylactic or anaphylactoid reactions caused by the induction drug,13–15 or rifampin16 are unlikely, given the lack of hypotension in the control groups. In no case, did the clinicians record urticaria or flushing, bronchospasm, or mucosal edema. One mechanism that is suggested to promote hypotension after propofol administration is related to its direct effect on venous smooth muscle tone, presumably through increased production and release of endothelial nitric oxide (NO).17 Rifampin might augment this effect by upregulating inducible NO synthase mRNA transcription.18 This increase in NO levels has only been demonstrated in vitro, but it does occur within 20 hours after exposure to clinically relevant concentrations of rifampin (10–100 µg/mL). The serum concentration of rifampin after 2 hours following a single 600-mg oral dose was reported to be 8.8 to 12 µg/mL19–21 and in another study 15.9 µg/mL,4 so the NO mechanism is a plausible explanation with the antibiotic concentrations likely present in our patient. The serum concentrations of rifampin in the study by Archer etal.4 decreased from 15.9 ± 6.5 µg/mL at 2 hours to 7.1 ± 4.3 at 8 hours, with 1.6 ± 1.6 µg/mL still detectable at 24 hours. This suggests that sufficient rifampin may be present to cause drug–drug interactions for a significant period of time after typical oral dosing.

Rifampin is commonly used for treatment of tuberculosis and less often for prophylaxis of staphylococcal infections and Neisseria meningitidis infections. It is rarely used for routine preoperative antimicrobial prophylaxis, which could explain why this interaction with propofol may not have been appreciated previously. Clinicians should be aware of this potentially dangerous interaction and, if rifampin is necessary, consider using alternative drugs for induction of anesthesia. A prospective study is desirable to investigate the mechanism of this drug–drug interaction.

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DISCLOSURES

Name: Hooman Mirzakhani, MD.

Contribution: This author helped in study design, conduct of study, data analysis, and manuscript preparation.

Attestation: Hooman Mirzakhani approved the final manuscript and is the archival author.

Name: Ala Nozari, MD, PhD.

Contribution: This author helped in study design, conduct of study, data analysis, and manuscript preparation.

Attestation: Ala Nozari attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Jesse M. Ehrenfeld, MD, MPH.

Contribution: This author helped in data collection and analysis.

Name: Robert Peterfreund, MD, PhD.

Contribution: This author helped in manuscript preparation.

Name: Michele Szabo, MD.

Contribution: This author helped in manuscript preparation.

Name: John Walsh, MD.

Contribution: This author helped in manuscript preparation.

Name: Yandong Jiang, MD, PhD.

Contribution: This author helped in manuscript preparation.

Name: Warren Sandberg, MD, PhD.

Contribution: This author helped in data collection and analysis.

Name: Carl Rosow, MD, PhD.

Contribution: This author helped in manuscript preparation.

Name: Jingping Wang, MD, PhD.

Contribution: This author helped in case report, study design, and manuscript preparation, and is the primary investigator.

This manuscript was handled by: Tony Gin, FANZCA, FRCA, MD.

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REFERENCES

1. Wehrli W. Rifampin: mechanisms of action and resistance. Rev Infect Dis. 1983;5:S407–11

2. Venkatesan K. Pharmacokinetic drug interactions with rifampicin. Clin Pharmacokinet. 1992;22:47–65

3. Turnidge J, Grayson ML. Optimum treatment of staphylococcal infections. Drugs. 1993;45:353–66

4. Archer GL, Armstrong BC, Kline BJ. Rifampin blood and tissue levels in patients undergoing cardiac valve surgery. Antimicrob Agents Chemother. 1982;21:800–3

5. Falagas ME, Fragoulis KN, Bliziotis IA. Oral rifampin for prevention of S. aureus carriage-related infections in patients with renal failure–a meta-analysis of randomized controlled trials. Nephrol Dial Transplant. 2006;21:2536–42

6. Dobzyniak MA, Fischgrund JS, Hankins S, Herkowitz HN. Single versus multiple dose antibiotic prophylaxis in lumbar disc surgery. Spine (Phila Pa 1976). 2003;28:E453–5

7. El-Tahan MR. Preoperative ephedrine counters hypotension with propofol anesthesia during valve surgery: a dose dependent study. Ann Card Anaesth. 2011;14:30–40

8. Dhungana Y, Bhattarai BK, Bhadani UK, Biswas BK, Tripathi M. Prevention of hypotension during propofol induction: a comparison of preloading with 3.5% polymers of degraded gelatin (Haemaccel) and intravenous ephedrine. Nepal Med Coll J. 2008;10:16–9

9. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–83

10. Morley AP, Nalla BP, Vamadevan S, Strandvik G, Natarajan A, Prevost AT, Lewis CM. The influence of duration of fluid abstinence on hypotension during propofol induction. Anesth Analg. 2010;111:1373–7

11. Berezhinskaia VV, Dolgova GV, Svinogeeva TP, Zebrev AI. Mechanism of hypotension induced by rifampicin during intravenous administration. Antibiot Khimioter. 1988;33:771–5

12. Muzi M, Berens RA, Kampine JP, Ebert TJ. Venodilation contributes to propofol-mediated hypotension in humans. Anesth Analg. 1992;74:877–83

13. Laxenaire MC, Gueant JL, Bermejo E, Mouton C, Navez MT. Anaphylactic shock due to propofol. Lancet. 1988;2:739–40

14. Belso N, Kui R, Szegesdi I, Kakuja M, Kapitány K, Kemény L, Bata-Csörgo Z. Propofol and fentanyl induced perioperative anaphylaxis. Br J Anaesth. 2011;106:283–4

15. Lawes EG, Davis A. Anaphylactoid reaction to propofol. Anaesthesia. 1993;48:446–7

16. Martínez E, Collazos J, Mayo J. Hypersensitivity reactions to rifampin. Pathogenetic mechanisms, clinical manifestations, management strategies, and review of the anaphylactic-like reactions. Medicine (Baltimore). 1999;78:361–9

17. Basu S, Mutschler DK, Larsson AO, Kiiski R, Nordgren A, Eriksson MB. Propofol (Diprivan-EDTA) counteracts oxidative injury and deterioration of the arterial oxygen tension during experimental septic shock. Resuscitation. 2001;50:341–8

18. Yuhas Y, Berent E, Ovadiah H, Azoulay I, Ashkenazi S. Rifampin augments cytokine-induced nitric oxide production in human alveolar epithelial cells. Antimicrob Agents Chemother. 2006;50:396–8

19. Verbist L, Gyselen A. Antituberculous activity of rifampin in vitro and in vivo and the concentrations attained in human blood. Am Rev Respir Dis. 1968;98:923–32

20. Furesz S, Scotti R, Pallanza R, Mapelli E. Rifampicin: a new rifamycin. 3. Absorption, distribution, and elimination in man. Arzneimittelforschung. 1967;17:534–7

21. Nitti V, Delli Veneri F, Ninni A, Meola G. Rifampicin blood serum levels and half-life during prolonged administration in tuberculous patients. Chemotherapy. 1972;17:121–9

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