|Year : 2017 | Volume
| Issue : 1 | Page : 182-187
Intravenous ephedrine, phenylephrine, and ketamine for attenuation of hypotension associated with induction of general anesthesia with propofol
Mostafa Mansour Hussein, Raham Hasan Mostafa, Ibrahim Mohamed Ibrahim
Department of Anesthesia, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Web Publication||3-Aug-2018|
Mostafa Mansour Hussein
5 Abdel-azim Salama Street, Nasr City, Cairo, 11727
Source of Support: None, Conflict of Interest: None
Background and objective Hypotension and bradycardia remain the major adverse effects of propofol during induction of general anesthesia. Several drugs were studied to prevent these adverse effects. In our study, we compare the effect of mixing ephedrine, phenylephrine, or ketamine with propofol to attenuate its hypotensive effect during induction of general anesthesia.
Materials and methods A total of 120 patients of both sexes between 20 and 50 years of age and ASA I–II physical status undergoing elective ambulatory surgeries under general anesthesia were included in our study. Patients were randomly allocated into four groups (30 patients each): group C (the control group), which received plain propofol; group E (the ephedrine group), which received 15 mg of ephedrine premixed with propofol; group Ph (the phenylephrine group), which received 100 μg of phenylephrine premixed with propofol; and group K (the ketamine group), which received 30 mg of ketamine premixed with propofol. In all groups, mean arterial blood pressure (MABP) and heart rate (HR) were recorded at baseline (before induction) and then every 1 min until 6 min after induction.
Results Addition of ephedrine, phenylephrine, or ketamine to propofol during general anesthesia induction can significantly attenuate hypotension and bradycardia. In the control group, the MABP dropped from 91.96±3 mmHg just before induction to 75.6±8.7 mmHg at 6 min after induction. HR in the control group dropped from 83.76±7.29/min just before induction to 75.3±12/min at 6 min after induction. The drop in MABP and HR were nonsignificant in the other three groups.
Conclusion Mixing propofol with ketamine, ephedrine, or phenylephrine before induction can attenuate its hypotensive and bradycardic effects.
Keywords: ephedrine, hypotension, ketamine, phenylephrine, propofol
|How to cite this article:|
Hussein MM, Mostafa RH, Ibrahim IM. Intravenous ephedrine, phenylephrine, and ketamine for attenuation of hypotension associated with induction of general anesthesia with propofol. Ain-Shams J Anaesthesiol 2017;10:182-7
|How to cite this URL:|
Hussein MM, Mostafa RH, Ibrahim IM. Intravenous ephedrine, phenylephrine, and ketamine for attenuation of hypotension associated with induction of general anesthesia with propofol. Ain-Shams J Anaesthesiol [serial online] 2017 [cited 2018 Nov 20];10:182-7. Available from: http://www.asja.eg.net/text.asp?2017/10/1/182/238454
| Introduction|| |
Propofol (2, 6 di isopropyl phenol) is considered the most commonly used short-acting intravenous anesthetic induction agent worldwide. Propofol possesses the advantage of smooth induction and rapid recovery. Besides its use in the induction and maintenance of general anesthesia, propofol is also used for sedation during regional anesthesia as well as sedation of patients in ICU .
Anesthesia induction with propofol is associated with significant hypotension and bradycardia. This decrease in blood pressure has been reported to be the result of direct myocardial depression, impaired baroreflex mechanism, and decreased systemic vascular resistance (due to venous and arterial vasodilatation) ,,.
Different methods have been attempted to prevent hypotension during propofol induction. These methods include slow injection of the drug, fluid preloading (colloid or crystalloid), or vasoactive drug administration (e.g. dopamine, dobutamine, ephedrine, phenylephrine, and ketamine) .
Ephedrine is a well-known indirect sympathomimetic drug. It exerts its action through indirect stimulation of adrenergic receptor system and increases the activity of noradrenaline at postsynaptic α and β receptors .
Prophylactic use of ephedrine was effective in attenuating the hypotensive effect of propofol during induction of general anesthesia. Ephedrine can be given either as intravenous bolus dose, intramuscular injection, or by means of continuous infusion . A large dose of ephedrine has demonstrated its effectiveness against propofol-induced hypotension, but with marked tachycardia .
Phenylephrine is a synthetic sympathomimetic drug, which acts directly on α1 adrenergic receptors. Phenylephrine has a minimal effect on β adrenergic receptors. It has some indirect action by increasing the release of norepinephrine. Phenylephrine dosage ranges from 50 to 200 μg intravenous to treat hypotension associated with regional anesthesia or peripheral vasodilatation .
Alternatively, ketamine can be used to attenuate the hypotensive effect of propofol injection through the direct stimulation of the sympathetic nervous system with increased sympathetic outflow. This results in increased heart rate (HR), and systemic and pulmonary arterial pressure ,.
The present study aimed to compare different drugs in the prevention of hypotension during induction of anesthesia using propofol as an induction agent in perianal surgery.
| Materials and methods|| |
This was a prospective, randomized, comparative, controlled study conducted on 120 patients of American Society of Anesthesiologist (ASA) physical status I and II between 20 and 50 years of age of either sex undergoing elective perianal surgery under general anesthesia. The study was conducted in Ain-Shams University Hospital during the period from January 2015 to November 2015.
Approval for the study was obtained from Ain-Shams University’s ethical committee, and written informed consent was taken from all patients after explaining the nature of the study. Patients with a history of hypertension (controlled or uncontrolled), cerebrovascular, cardiac, respiratory, hepatic, or renal diseases, those with thyrotoxicosis, those with allergy to the study drugs, those undergoing therapy with vasoactive medications, and patients with Mallampati III or IV, morbid obesity (BMI>35 kg/m2), pregnancy, or any hypovolemic condition were excluded from the study. Moreover, patients with allergy to eggs or soy were excluded.
All patients in this study were subjected to a detailed preanesthetic evaluation. All basic investigations according to our hospital protocol (e.g. fasting blood sugar, serum hemoglobin, kidney function tests, liver function tests, chest radiographs, and ECG) were carried out. In the operating room, standard monitoring (ECG, HR, blood pressure, pulse oximetry, and end-tidal CO2) was established. A peripheral intravenous cannula was inserted and secured. A volume of 5–7 ml/kg of Ringer’s solution was administered over a period of 10 min. Patients were randomly allocated into four study groups (30 patients each) using the sealed envelope technique. After preoxygenation for 3 min, induction with propofol was carried out as follows: in group C (the control group), plain propofol (2 mg/kg in all groups) was given intravenously over 20–30 s; in group E (the ephedrine group), ephedrine (15 mg) premixed with propofol was given intravenously over 30 s; in group Ph (the phenylephrine group), phenylephrine (100 μg) premixed with propofol was given intravenously over 30 s; and, finally, in group K (the ketamine group), ketamine (30 mg) premixed with propofol was given intravenously over 30 s. Subsequently, fentanyl (1 μg/kg) and atracurium besylate (0.5 mg/kg) were given intravenously in all groups. The usual maintenance and replacement fluid (Ringer’s lactate solution) was started.
Mean arterial blood pressure (MABP) and HR were recorded at baseline (before induction) and then every 1 min until 6 min after induction. The physician who administer propofol and the investigator who recorded vital signs from the patients were blinded to the randomization process (i.e. double blinded). During this period, bag and mask ventilation was used to maintain oxygen saturation greater than 95% and no laryngeal mask intubation was performed. Hypotension was considered when there was a fall in mean blood pressure of at least 20% from baseline. Hypotension was treated with rapid infusion of Ringer’s lactate solution. Moreover, the cases with a decrease or increase in HR (20% change from baseline) were recorded.
After complete relaxation, an appropriately sized laryngeal mask airway was inserted and connected to the circuit. After confirming the position and fixation of the laryngeal mask airway, positive-pressure ventilation was started with the administration of 0.5–1% isoflurane to continue anesthesia and surgery.
In a one-way analysis of variance study, sample sizes of 24, 24, 24, and 24 were obtained from the four groups whose means are to be compared. The total sample of 96 participants achieves 82% power to detect differences among the means of hemodynamic variables using an F-test with a 0.05000 significance level. The size of the variation in the means is represented by their SD, which is 5.72. The common SD within a group is assumed to be 15.00. A total of 25 patients per group were included to replace any dropouts.
Data were analyzed using SPSS 21.0 for Windows (SPSS Inc., Chicago, Illinois, USA). Analysis of variance was used to compare the four groups for quantitative parametric data with post-hoc Tukey’s test performed if there was a significant difference among the groups. The χ2-test was used for comparison of qualitative data. Continuous parametric data were presented as mean±SD, and categorical data were presented as number of patients. P-values of less than 0.05 were considered significant.
| Results|| |
The demographic data of the patients in the four groups were comparable and there were no statistically significant differences as regards age, weight, sex, ASA, and type of surgery (P>0.05) ([Table 1]).
[Table 2] shows comparison of MABP among the four groups. There were statistically significant differences between group C and the other three groups starting from the second minute until the sixth minute after propofol administration (P<0.05). We noticed that the peak difference was in the third and fourth minute.
|Table 2 Comparison (analysis of variance) of mean arterial blood pressure|
Click here to view
[Table 3] shows comparison of HR in the four groups. The HR decreased in group C and group Ph with respect to baseline, whereas HR increased in group E and group K. The change in HR at 1 min was not statistically significant (P>0.05), but significant at 2, 3, 4, 5, and 6 min (P<0.05).
[Table 4] shows the number of patients developing hypotension among the four groups. Greater number of patients in the control group developed hypotension (which is defined as ≥20% drop in MABP from baseline) especially at the third and fourth minutes and was statistically significant (P<0.05) (starting from second minute). At sixth minute, 22 patients in the control group developed hypotension, whereas no patients in the other three groups developed any hypotension.
| Discussion|| |
The present study aimed to compare different drugs (ephedrine, phenylephrine, and ketamine) in the prevention of hypotension during induction of anesthesia using propofol as an induction agent in ambulatory surgery. All patients in the four groups were comparable as regards age, weight, sex distribution, ASA classification, and type of ambulatory surgery.
The most common time at which bradycardia and hypotension occur during anesthesia is immediately after induction before intubation, with the peak effect of induction drugs with minimal surgical stimulation anticipated. Thus, we measured the MABP and HR every minute after induction of anesthesia (the peak effect of propofol) and up to 6 min to examine the safety of the given medications to prevent these side-effects when peak of change in HR and blood pressure is anticipated.
In our study, we detected that intravenous prophylactic ephedrine, phenylephrine, and ketamine were more effective in preventing hypotension during propofol induction. We observed that the mean arterial pressure decreased only in the control group during induction of anesthesia with propofol, but no decrease occurred in the other three groups. Subsequently, a higher number of patients had experienced hypotension after propofol induction in the control group when compared with the other three groups.
We also observed a decrease in HR in the control group, whereas HR was increased in the ephedrine and ketamine groups and it was less than 10% of the baseline and statistically significant.
The observation in our study also suggests that addition of phenylephrine at a dose of 100 μg is associated with a slight decrease in HR due to its vagotonic effect as compared with other groups.
As regards the ephedrine group, our findings are consistent with the study by El-Tahan  in showing the effect of ephedrine in preventing hypotension induced by propofol and fentanyl. They used 0.07, 0.1, and 0.15 mg/kg intravenous ephedrine in patients operated for valve surgery. However, in this study, marked side-effects such as tachycardia and the risk for myocardial ischemia were detected. These observations were attributed to their method of patient selection, as patients aged over 60 years with ASA III and IV were included in the study.
In another study by Malla et al. , they concluded that ephedrine markedly attenuates but does not prevent the decrease in blood pressure caused by induction.
Dutta et al.  proved that prophylactic intravenous injection of 0.2 mg/kg of ephedrine just before induction significantly attenuated but did not fully prevent the decrease in blood pressure.
The results of our study are also in line with the findings of Michelsen et al. , who studied women above 60 years of age scheduled for minor gynecological surgeries. In all, 0.1 and 0.2 mg/kg of ephedrine were used before anesthesia induction with propofol and fentanyl by 1 min. They concluded that both doses of ephedrine can protect against hypotension.
The results in the present study are comparable to those of Masjedi et al. , who found that the administration of high ephedrine dose (0.15 mg/kg) has a marked effect in preventing hypotension and bradycardia after induction of anesthesia with propofol and remifentanil. Dhungana et al.  also found that prophylactic intravenous ephedrine at a dose of 0.2 mg/kg significantly attenuated but did not prevent the decrease in blood pressure during propofol and fentanyl induction. Gamlin et al.  found that 15 or 20 mg of ephedrine premixed with 20 ml of 1% propofol maintained blood pressure at preinduction levels, whereas ephedrine 10 mg was insufficient to prevent hypotension.
Gamlin et al.  and El-Beheiry et al.  reported marked tachycardia associated with the use of ephedrine in combination with propofol in most of the patients. This difference could be correlated with higher doses of ephedrine (20 and 25 mg) in their study than in ours (15 mg).
However, Agarwal et al.  concluded that preoperative ephedrine administration failed to abolish propofol-induced hypotension. This may be attributed to the small dose they used (70 μg/kg).
Multiple previous studies demonstrated that phenylephrine at a dose of 50 to 200 μg intravenously can be administered to adults to counteract the decrease in blood pressure that accompanies sympathetic nervous system blockade produced by regional anesthesia and peripheral vasodilatation that accompanies administration of injected or inhaled anesthetics .
Imran and colleagues observed that addition of phenylephrine at a dose of 50 μg was ineffective to completely abolish the hypotensive effects; however, the dose of 100 μg was very effective. Phenylephrine at 100 μg dose maintained systolic blood pressure up to 4 min after induction, which is the period of maximum cardiovascular instability caused by propofol .In obstetric patients, phenylephrine prevented spinal-induced hypotension, bradycardia, and decrease in cardiac output while maintaining systolic, mean, and diastolic blood pressure. However, these studies were conducted in obstetric patients, who are young and healthy with no cardiac problems .
Ketamine increases HR and arterial blood pressure through stimulation of the sympathetic nervous system. The clinical effects of propofol and ketamine are complementary. When ketamine and propofol are administered in combination, doses of both agents decrease and unwanted effects are minimized .
As regards ketamine, our results correlate with that of Furuya and colleagues. Their results showed a smaller increase in systolic, diastolic, and mean arterial pressure just after intubation up to 3 min after intubation when ketamine–propofol combination was given .
One limitation to our study is present. This limitation is that all participants were healthy and of ASA physical status I and II, with no history of cardiovascular diseases.
| Conclusion|| |
We concluded that mixing ephedrine and ketamine with propofol reduced the incidence of hypotension in a significant number of patients as compared with the control group. Phenylephrine also reduced the incidence of hypotension but with little bradycardia.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Smith I, White PF, Nathanson M, Gouldson R. Propofol. An update on its clinical use. Anesthesiology 1994; 81:1005–1043.
Muzi M, Berens RA, Kampine JP, Ebert TJ. Venodilation contributes to propofol-mediated hypotension in humans. Anesth Analg 1992; 74:877–883.
Robinson BJ, Ebert TJ, O’Brien TJ, Colinco MD, Muzi M. Mechanisms whereby propofol mediates peripheral vasodilation in humans. Sympathoinhibition or direct vascular relaxation? Anesthesiology 1997; 86:64–72.
Cullen PM, Turtle M, Prys-Roberts C, Way WL, Dye J. Effect of propofol anesthesia on baroreflex activity in humans. Anesth Analg 1987; 66:1115–1120.
Reves JG, Glass SA. Non-barbiturates intravenous anesthetics. In: Miller RD, editor. Anaesthesia
. 3rd ed. Philadelphia: Churchill Livingstone; 1990. 243–280.
Ma G, Bavadekar SA, Davis YM, Lalchandani SG, Nagmani R, Schaneberg BT et al.
Pharmacological effects of ephedrine alkaloids on human alpha(1)- and alpha(2)-adrenergic receptor subtypes. J Pharmacol Exp Ther 2007; 322:214–221.
Cyna AM, Andrew M, Emmett RS, Middleton P, Simmons SW. Techniques for preventing hypotension during spinal anaesthesia for caesarean section. Cochrane Database Syst Rev 2006 Oct 18; (4):CD002251.
Michelsen I, Helbo-Hansen HS, Køhler F, Lorenzen AG, Rydlund E, Bentzon MW. Prophylactic ephedrine attenuates the hemodynamic response to propofol in elderly female patients. Anesth Analg 1998; 86:477–481.
Thomas DG, Robson SC, Redfern N, Hughes D, Boys RJ. Randomized trial of bolus phenylephrine or ephedrine for maintenance of arterial pressure during spinal anaesthesia for Caesarean section. Br J Anaesth 1996; 76:61–65
Katz RL, Levy A, Slepian B, Sobel B, Lagasse RS. Hemodynamic stability and ketamine-alfentanil anesthetic induction. Br J Anaesth 1998; 81:702–706.
Tweed WA, Minuck MS, Mymin D. Circulatory response to ketamine anesthesia. Anesthesiology 1972; 37:613–619.
El-Tahan MR. Preoperative ephedrine counters hypotension with propofol anesthesia during valve surgery: a dose dependent study. Ann Card Anaesth 2011; 14:30–40.
] [Full text]
Malla S, Andrabi R, Ashraf S, Saleem B. Prevention of hypotension caused by induction of anaesthesia with propofol, a comparison of preloading with 3.5% polymers of degraded gelatin solution, crystalloid (Ringer lactate) & intravenous ephedrine. J Evol Med Dent Sci 2015; 4:365–374.
Dutta V, Ahmad M, Gurcoo S, Ommid M, Qazi MS. Prevention of hypotension during induction of anesthesia with propofol and fentanyl: comparison of preloading with crystalloid and intravenous ephedrine. IOSRJDMS 2012; 1:26–30.
Masjedi M, Zand F, Kazemi AP, Hoseinipour A. Prophylactic effect of ephedrine to reduce hemodynamic changes associated with anesthesia induction with propofol and remifentanil. J Anaesthesiol Clin Pharmacol 2014; 30:217–221.
] [Full text]
Dhungana Y, Bhattarai BK, Bhadani UK, Biswas BK, Tripathi M. Prevention of hypotension during propofol induction: a comparison for preloading with 3.5% polymers of degraded gelatin (Haemaccel) and intravenous ephedrine. Nepal Med Coll J 2008; 10:16–19.
Gamlin F, Vucevic M, Winslow L, Berridge J. The haemodynamic effects of propofol in combination with ephedrine. Anaesthesia 1996; 51:488–491.
El-Beheiry H, Kim J, Milne B, Seegobin R. Prophylaxis against the systemic hypotension induced by propofol during rapid-sequence intubation. Can J Anaesth 1995; 42:875–878.
Agarwal A, Sharma K, Parashar S, Sharma A, Meena M. Prevention of hypotension during propofol induction: a comparison of preloading with Ringer lactate and intravenous ephedrine. J Evol Med Dent Sci 2013; 2:6640–6650.
Imran M, Khan FH, Khan MA. Attenuation of hypotension using phenylephrine during induction of anaesthesia with propofol. J Pak Med Assoc 2007; 57:543–547.
Brooker RF, Butterworth JF IV, Kitzman DW, Berman JM, Kashtan HI, McKinley AC. Treatment of hypotension after hyperbaric tetracaine spinal anesthesia. A randomized, double-blind, cross-over comparison of phenylephrine and epinephrine. Anesthesiology 1997; 86:797–805.
Okuyama K, Inomata S, Okubo N, Watanabe I. Pretreatment with small-dose ketamine reduces predicted effect-site concentration of propofol required for loss of consciousness and Laryngeal Mask Airway insertion in women. J Clin Anesth 2011; 23:113–118.
Furuya A, Matsukawa T, Ozaki M, Nishiyama T, Kume M, Kumazawa T. Intravenous ketamine attenuates arterial pressure changes during the induction of anaesthesia with propofol. Eur J Anaesthesiol 2001; 18:88–92.
[Table 1], [Table 2], [Table 3], [Table 4]