Regimen for Target-controlled Infusion Decreasing Remifentanil-induced cough

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Regimen for Target-controlled Infusion

Decreasing Remifentanil-induced Cough

by

In Kyong Yi

Major in Medicine

Department of Medical Sciences

The Graduate School, Ajou University

Regimen for Target-controlled Infusion

Decreasing Remifentanil-induced Cough

by

In Kyong Yi

A Dissertation Submitted to The Graduate School of

Ajou University in Partial Fulfillment of the Requirements

for the Degree of Master of Medicine

Supervised by

Young Joo Lee, M.D., Ph.D.

Major in Medicine

Department of Medical Sciences

The Graduate School, Ajou University

This certifies that the dissertation

of In Kyong Yi is approved.

SUPERVISORY COMMITTEE

Young Joo Lee

Bong Ki Moon

Jong Yeop Kim

The Graduate School, Ajou University

June 23rd, 2011

- ABSTRACT -

Regimen for Target-controlled Infusion Decreasing

Remifentanil-induced Cough

Background: This study evaluated the effectiveness of target-controlled infusion (TCI) of

remifentanil using different stepwise increases of central effect-site concentration (Ceff) on

cough prevention.

Methods: As a preliminary study, 140 patients were randomly assigned to receive

remifentanil targeting 2-stepwise increase of Ceff (1.0 to 4.0, or 2.0 to 4.0 ng/ml). From the

result of the preliminary study, 3-stepwise increase TCI (1.0 to 2.0, then to 4 ng/ml) was postulated and compared to direct targeting with 4.0 ng/ml TCI, randomly applied to another 140 patients. Episodes of cough were recorded and graded as mild (1–2), moderate (3–4), or severe (5 or more).

Results: In Group R1-4, one patient (1.5%) coughed at the first step, and the other 5

patients (7.3%) coughed during the second step. In Group R2-4, 9 patients (13.2%) coughed

during the first step; but none coughed during the next step. Only 1 patient showed a mild cough during the 3-stepwise increase TCI in Group R1-2-4, which significantly reduced the

Conclusions: Stepwise increase of TCI of remifentanil could reduce the incidence of

remifentanil-induced coughing, and 3-stepwise increase of TCI could nearly abolish remifentanil-induced coughing.

Key words : Remifentanil, Cough, Target-controlled infusion, Opioid

TABLE OF CONTENTS

ABSTRACT ··· ⅰ

TABLE OF CONTENTS ··· iii

LIST OF FIGURES ··· iv

LIST OF TABLES ··· v

Ⅰ. INTRODUCTION ··· 1

Ⅱ. MATERIALS AND METHODS ··· 2

A. MATERIALS ··· 2 1. SUBJECTS ··· 2 2. PREPARATION ··· 2 B. METHODS ··· 3 1. SETTING ··· 3 2. STATISTICS ··· 4 III. RESULTS ··· 6 IV. DISCUSSION ··· 14 Ⅴ. CONCLUSION ··· 18 REFERENCES ··· 19 국문요약 ··· 22

LIST OF FIGURES

Fig. 1.

CONSORT diagram showing the flow of patients through the study.

Fig. 2.

Time course of the predicted plasma (black dotted curve) and central

effect-site (gray curve) concentration of remifentanil during target

controlled-infusion.

Fig. 3.

Time course of prediced plasma (black dotted curve) and central effect-site

(gray curve) concentration of remifentanil during target

controlled-infusion.

Table 1.

Characteristics of patients receiving different remifentanil infusions

to target effect-site concentrations.

Table 2.

Bolus dose for target-controlled infusion of remifentanil.

Table 3.

Incidence, severity, and characteristics of remifentanil-induced

I. INTRODUCTION

Remifentanil, one of the narcotic opioids traditionally known as an analgesic and antitussive agent, sometimes causes cough during induction of anaesthesia, as with other opioids of the fentanyl series.( Agarwal, 2007; Kim, 2010; Lim, 2010; Cho, 2010) The incidence of cough after intravenous administration of remifentanil varies between 25 and 34%.( Kim, 2010; Lim, 2010; Cho, 2010) Although remifentanil-induced cough is usually benign and self-limiting, it may disrupt the smooth induction of anaesthesia and might cause harm to predisposed patients with increased intracranial, intra-ocular, and intra-abdominal pressures, and unstable haemodynamics.

Pretreatment of drugs known to reduce airway reactivity, such as lidocaine or propofol, could reduce incidence of remifentanil-induced cough, as in fentanyl-induced cough.( Pandey, 2004; Kim, 2008; Kim, 2010) However, these pharmacological preventive interventions do not appear to have achieved the maximal avoidance of cough. Our previous study demonstrated the relationship between the occurrence of cough and the time course of the plasma (Cp) and central effect-site (Ceff) concentration of remifentanil during

target-controlled infusion (TCI) of remifentanil.(Kim, 2010) Also, pharmacokinetic (PK) and pharmacodynamic (PD) approaches, maintaining the balance between the tussive and antitussive arm of remifentanil, were thought to be essential for prevention of cough. Therefore, this study was designed to build a remifentanil TCI regimen for maximal avoidance of remifentanil-induced cough, without any requirement of additional pharmacologic preventive measures.

II.

MATERIALS AND METHODS

A. Material

1. Subjects

This study was approved by the institutional review board, and written informed consents were obtained from all patients. A total of 280 patients, ASA physical status I or II, ages 18-70 years, undergoing general anaesthesia for gynaecologic surgery, were enrolled in the study. Exclusion criteria included a body weight exceeding 20% of ideal, a history of bronchial asthma or chronic obstructive pulmonary disease, respiratory tract infection, or hypertension treated with angiotensin converting enzyme inhibitors. Patients who smoked were included in the study.

2. Preparation

No premedication was administered prior to surgery. A 20-gauge cannula was inserted into the forearm or dorsum of the hand, and connected to a three-way stopcock prior to arrival in the operating theatre. Upon arrival in the operating theatre, all patients were monitored with electrocardiogram, pulse oximeter, noninvasive blood pressure, and capnography.

Infusion of remifentanil was prepared in a 60 ml syringe (BD 60ml Syringe, Luer-LokTM _{Tip, BD, USA) using 2.0 mg of remifentanil (Ultiva}TM_{, GlaxoSmithKline, Parma,}

Italy) diluted with 50ml normal saline to make a 40 μg/ml solution. A TCI pump (Orchestra®_{, Fresenius Vial, Brezins, France) with the pharmacokinetic model of Minto and}

syringe pump was set to 1,200 ml/hr and maximal permissible plasma concentration of remifentanil to 50.0 ng/ml, thus, an overshoot of plasma concentration was permitted, avoiding interference in maximal delivery by the TCI pump. Following insertion of the syringe into the TCI pump, we performed ‘purge the syringe and infusion line’, and connected the syringe extension line to the three-way stopcock of the patient just before initiation of infusion.

B. Methods

1. Setting

As a preliminary study, 140 patients were randomly assigned to one of the two groups using computer-generated random numbers. Group R1-4 received remifentanil TCI, initially

targeting 1.0 ng/ml of Ceff, and Group R2-4 targeting 2.0 ng/ml of Ceff. When Ceff reached

each target effect-site concentration (Ct-eff), Ct-eff was increased to 4.0 ng/ml. Immediately

after infusion of remifentanil, an observer, blinded to the regimens of remifentanil infusion, recorded the occurrence of cough as 'yes' or 'no', and the onset time of cough (from the start of infusion to the first cough). And the duration (from the start of cough to cessation of cough) was also recorded. Cough was assessed until 1 min after Ceff reached the final Ct-eff,

while maintaining pseudo steady-state concentration. Depending upon the number of coughs observed, cough severity was graded as no (0), mild (1–2), moderate (3–5), or severe (> 5). The amount of remifentanil infused at each step, and total duration to final target were recorded during the study. Assisted mask ventilation with oxygen was applied if desaturation was observed (SpO2 < 95%).

Using PHARMACOKINETIC (PK) and PHARMACODYNAMIC (PD) software (Asanpump, ver 1.5, Ulsan University, Seoul, Korea), we performed TCI simulations for patients. Individual covariates were entered and the Minto PK/PD model of remifentanil was also used, and data refresh interval was set to 2 s. Relationships between the occurrence of coughing and the time course of Cp and Ceff-CNS of remifentanil were evaluated.

Based on the results of this preliminary study, we have built a regimen in anticipation of maximal reduction of the incidence of coughing (less than 5% of incidence), which was a 3-stepwise increase of Ct-eff, starting at 1.0 ng/ml of Ct-eff, increased to 2.0 ng/ml after 30 s,

when Ceff reached the target, and was finally increased to 4.0 ng/ml. Another 140 patients

were randomly assigned to one of the two groups. Group R1-2-4 received remifentanil using

this 3-stepwise increase TCI, and Group R4 received a one-step increase TCI with direct

targeting of 4.0 ng/ml of Ceff from the start of infusion. Evaluation of cough and TCI

simulations were performed in the same manner described above.

Loss of consciousness (LOC), apnoea, and chest wall rigidity after remifentanil injection were observed. Mean arterial pressure (MAP), heart rate (HR), and SpO2 were compared

upon arrival in the operating theatre (baseline) with those at 5 min after remifentanil infusion. Following assessment of cough, propofol TCI was titrated to induce loss of consciousness and rocuronium was administered for intubation.

2. Statistics

Considering the incidence of remifentanil-induced cough to be 27.6%, (Kim, 2008) and assuming the incidence of cough to be less than 5% after application of a regimen, this study required at least 63subjectsper group at the 5% level of significance and 90% power of test. The sample size was increased to 70 patients per group in order to account for up to 10% losses from the study. Statisticalanalyses were performed using SPSS 13.0 for Windows (SPSS Inc, Chicago, IL, USA). Data are reported as the mean ± SD or number of patients. Continuous data were compared using a two tailed Student’s t-test or by repeated measures ANOVA with Bonferroni correction. Categorical data were analysed using a Fisher’s exact test or chi-square test where appropriate. A P value < 0.05 was considered significant.

III. RESULTS

Among 280 enrolled patients, 7 patients did not complete study due to technical problems, such as IV line obstruction, disconnection, and TCI device alarm (Fig. 1). There were no differences between groups in terms of patient characteristics and smoking status (Table 1). Infused amounts of remifentanil and total duration to 4.0 ng/ml of Ceff during

remifentanil TCI of the preliminary studies are shown in (Table 2). Incidence, severity, and characteristics of the cough are shown in (Table 3). In Group R1-4, one patient (1.5%)

coughed at the first step, and the other 5 patients (7.3%) coughed during the second step, increasing to 4.0 ng/ml of Ct-eff. Mean onset time of cough of these patients was 111.2 s

after the start of infusion; however, this was also 21.2 s after the start of the second step. In Group R2-4, 9 patients (13.2%) coughed during the first step; but none coughed during the

next step. Neither group showed severe cough. Time courses of the Cp and Ceff, and the

occurrence of cough in Group R1-4 and R2-4 are illustrated in (Fig. 2). Cp and Ceff of

Assessed for eligibility (n=312)

Randomized (n=140)

Excluded (n=32)

Not meeting inclusion criteria (n=17) Refuse to participate (n=12) Other reasons (n=3)

Group R1-4 (n=70 )

Not receive intervention (n=2)

Randomized (n=140)

Analysed (n=68) Excluded from analysis

(n=0)

Group R2-4 (n=70 )

Not receive intervention (n=2)

Group R1-2-4 (n=70 )

Not receive intervention (n=3)

Group R4 (n=70 )

Not receive intervention (n=0) Analysed (n=68)

Excluded from analysis (n=0)

Analysed (n=67) Excluded from analysis

(n=0)

Analysed (n=70) Excluded from analysis

(n=0)

Table 1. Characteristics of patients receiving different remifentanil infusions to target effect-site concentrations. Preliminary study R1-2-4 (n = 69) R4 (n = 70) R1-4 (n = 68) R2-4 (n = 68) Age (yr) 41.3 ± 7.6 39.0 ± 10.6 40.2 ± 9.8 40.7 ± 9.9 Weight (kg) 59.3 ± 8.9 58.0 ± 7.5 58.2 ± 8.0 60.1 ± 11.1 Height (cm) 160.1 ± 6.1 160.0 ± 5.4 159.0 ± 4.8 160.0 ± 6.4

ASA class (I/II) 55/13 52/16 54/13 57/13

Smoking history

None 59 55 57 60

Former 4 6 5 4

Current 5 7 5 6

Pack-year 4.3 ± 2.2 4.5 ± 2.0 4.2 ± 2.6 4.7 ± 2.3

Table 2. Bolus dose for target-controlled infusion of remifentanil. Preliminary study R1-2-4 (n = 67) R4 (n = 70) R1-4 (n = 68) R2-4 (n = 68)

Remifentanil at each step (μg/kg)

1st _{step 0.26 ± 0.03 0.52 ± 0.05 0.26 ± 0.03 1.03 ± 0.15}

2nd _{step 0.82 ± 0.09 0.60 ± 0.07 0.27 ± 0.03}

3rd _{step 0.59 ± 0.09}

Total (μg/kg) 1.08 ± 0.12 1.12 ± 0.11 1.12 ± 0.14* 1.03 ± 0.15 Time to 4.0 ng/ml of Ceff (min) 2.9 ± 0.1 2.8 ± 0.1 3.2 ± 0.1* 1.5 ± 0.1

Values represent mean ± SD.

Table 3. Incidence, severity, and characteristics of remifentanil-induced cough. Preliminary study R1-2-4 (n = 67 R4 (n = 70) R1-4 (n = 68) R2-4 (n = 68) Total 6 (8.8%) 9 (13.2%) 1 (1.5%)* 20 (28.5%) Severe 0 0 0 5 Moderate 4 3 0 5 Mild 2 6 1 10

Onset at each step (s) 1st _{step 35.0 26.3 ± 8.1 - 21.6 ± 8.9} 2nd _{step 21.2 ± 9.7 - 15.0 -} 3rd _{step - - - -} Duration (s) 2.5 ± 1.5 1.6 ± 0.7 1.0 3.0 ± 2.1 Number of cough 3.7 ± 1.8 2.0 ± 0.9 1.0 4.0 ± 3.1

Values represent the number of patients (percentage) or mean ± SD. *P < 0.001 compared with Group R4.

Infused amounts of remifentanil and total duration to the final targets in Group R1-2-4

and R4 are also shown in (Table 2). The total amount of infused remifentanil and time to

4.0 mg/ml of Ceff were significantly greater in Group R1-2-4 compared to Group R4 (P <

patient showed a mild cough during the 3-stepwise increase TCI in Group R1-2-4, which

significantly reduced the incidence of cough, compared with Group R4 (P < 0.001). Time

courses of the Cp and Ceff, and the occurrence of cough of Group R1-2-4 and R4 are illustrated

in (Fig. 2). Cp and Ceff of patients who coughed in Group R4 were 9.9 ± 1.72 ng/ml and 2.3

± 0.73 ng/ml, respectively.

In all groups, coughing started between 5 and 40 s after the start of each step. The maximum number of coughs was 12, and one patient of Group R4 showed symptoms

suggesting opioid-induced muscle rigidity, which was relieved after administration of propofol and rocuronium. None of the patients showed LOC or apnoea during the study. MAP, HR, and SpO2 did not differ significantly between before and after remifentanil TCI,

Fig.2. Time course of the predicted plasma (black dotted curve) and central effect-site (gray curve) concentration of remifentanil during target controlled-infusion. Target

effect-site concentration (gray dotted line) was increased in a step-wise manner from 1.0 to 4.0 ng/ml (left graph), and 2.0 to 4.0 ng/ml (right graph). The scattered plot shows the predicted plasma (○) and central effect-site (●) concentration of each individual at the onset of coughing.

Fig.3. Time course of the predicted plasma (black dotted curve) and central effect-site (gray curve) concentration of remifentanil during target controlled-infusion. Target

central effect-site concentration (gray dotted line) was increased in a step-wise manner from 1.0 to 2.0 and to 4.0 ng/ml (left graph), and was directly increased to 4.0 ng/ml (right graph). The scattered plot shows the predicted plasma (○) and central effect-site (●) concentration of each individual at the onset of coughing.

IV. DISCUSSION

When initiating intravenous infusion of remifentanil targeting Ceff during induction of

anaesthesia, the regimen using multiple stepwise increase of Ceff could prevent severe

remifentanil-induced coughing and significantly reduce the incidence of coughing, compared to the method of direct increase to a final target of 4.0 ng/ml of Ceff.

Among previous studies of opiod-induced cough, several are based on different methods of opioid injection. Schapermeier et al. reported that intravenous injection speeds of 1.5 μg/kg fentanyl did not influence the incidence of cough.(Schapermeier, 2008) However, Lin et al. reported that prolonged injection time of fentanyl decreased the incidence of cough.(Lin, 2005) Chen et al. demonstrated a decreasing incidence of cough for the intravenous injection rate of fentanyl and the influence of injection site on the cough.(Chen, 2009) A pre-emptive small dose of 25 μg/kg of fentanyl was reported to significantly reduce cough, followed by 125 μg/kgof fentanyl.(Hung, 2010) Lim et al. reported that administration of graded escalation of Ceff of remifentanil effectively suppressed the cough,

and their method and result were quite similar to those of our study.(Lim, 2010) However, most of these studies are focused on simply decreasing the incidence. Therefore, we attempted to investigate the relationship between provocation and suppression of cough in the context of PK/PD.

In putting the results of our preliminary study together with the previous simulation work,1 _{we were able to make tentative conclusions as follows: (1) Remifentanil-induced}

ng/ml (bolus of 0.82 μg/kg) while Ceff was maintained at 1.0 ng/ml, 7.3% (5/68) of patients

coughed. That is, 1.0 ng/ml of Ceff was not considered sufficient for prevention of coughing.

(3) When there was no remifentanil in the body, 0.52 μg/kg of remifentanil, in order to increase to 2.0 ng/ml of Ct-eff, made 13.2% of patients cough. However, if only Ceff was

maintained at 2.0 ng/ml, none of the patients coughed, even though a similar amount was administered (0.60 μg/kg) in order to increase to 4.0 ng/ml of Ceff. As a result, we were

able to anticipate that with addition of one more step, infusion of 1/3 increment Ceff in the

second step of R1-4, incidence at the second step might decrease by less than 2%, and overall

incidence might decrease by less than 5%, which was proposed as a final endpoint of cough incidence in this study. Using this 3 stepwise increase of TCI, one patient showed just one cough, and we were able to significantly decrease the incidence of cough. This regimen, of course, would be somewhat cumbersome in a routine clinical setting, because it requires that the targets be properly increased following the time elapsed. However, all TCI pumps display Cp, Ceff, and Ct-eff in real time, and some delay of Ct-eff increase might be beneficial

because it offers enough time for reaching the pseudo-steady state of remifentanil.

Simulations of the infusion regimens used during the study have shown the time courses of Cp and Ceff. Coughing also showed a tendency to develop while Cp was maintained

higher than Ceff, and as discrepancies between Cp and Ceff became smaller, or during the

steady-steady equilibrium state, coughing never occurred (Fig. 2, 3). Meanwhile, we found that the concentration-response relationship was difficult to account for, because the scattered plots of Cp of patients who coughed were not distributed around the peaks on visual

of Cp was also widely distributed. Intravascular space might not be the action site of

coughing, and that in order to trigger cough, remifentanil should diffuse from the intravascular space into the cough receptor sites, somewhere in the extra-vascular pulmonary structures. Therefore, in order to describe the concentration at the cough-triggering site, additional tussive effect-site compartment would be helpful to describe the PK/PD relationship of cough.

One of the findings associated with remifentanil-induced coughing that attracted our attention is its very rapid onset. Occurrence of coughing was as fast as 5-6 s in 3 patients of Group R4. Coughing occurred prior to completion of the injection of a whole bolus amount

of remifentanil. During this short interval, it could not be believed that remifentanil, injected into the vein of the dorsum of the hand or forearm, reached the central nervous system (CNS). Hoffmann et al. reported that ‘arm-to-head time’, the interval between the start of infusion of the echo-contrast agent injected into the antecubital vein and the beginning of signal amplification in the carotid artery, was 14.3 ± 3.0 s (min-max 9.0-22.0 s).(Hoffmann, 2000) Blumgart et al. reported that an active deposit of radium injected into the antecubital vein had been detected in the right chamber of the heart at 2.5- 14.0 s (arm-to-heart time), and pulmonary circulation time was estimated as 5.5 - 17.5 s.(Blumgart, 1927) Therefore, the possibility that remifentanil could have entered the CNS within 5 s is considered to be very low. Rather, it is supposed that remifentanil triggered coughing during pulmonary circulation. These cough-onset data might hold some important clues to a tussive effect via a peripheral acting mechanism. This peripheral tussive mechanism offers certain logic to our multi-stepwise increase regimen. Priming a small bolus amount

of remifentanil that is not sufficient to trigger cough, while passing the pulmonary circulation, eventually enters the systemic circulation and the drug will reach the CNS. Thereafter, if only the Ceff of the CNS increases up to a level sufficient for inhibition of

cough, coughing will never occur, even though the infusion of a large amount of remifentanil follows.

Several caveats require discussion here. First, we must consider the large variation of remifentanil concentration in the body during the initial rapidly mixing period immediately after injection into the vein.(Egan, 1996) In particular, considering its onset time, the predicted concentrations in the plasma and lung could be much different from the measured concentrations. Prior to entry into the central circulation, remifentanil might be diluted into the volume, which is different from that of the central compartment. Second, the target concentrations of remifentanil of this study were limited only to 1.0, 2.0, and 4.0 ng/ml. And we considered 2.0 ng/ml of Ceff as an effective antitussive concentration. However, it

is not guaranteed for higher targets. Therefore, more attention should be paid when high concentrations of remifentanil are targeted in clinical settings.

V. CONCLUSION

In conclusion, in this study, we wanted to build a regimen for remifentanil in anticipation of reducing the incidence of remifentanil-induced cough, based on analysis using PK/PD approaches, and, as a result, a multiple-stepwise increased TCI of remifentanil could effectively prevent coughing without other pharmacologic interventions.

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speed: a randomized study. Acta Anaesthesiol Scand 52: 1071-5, 2008

Remifentanil 유발 기침을 줄이기 위한 목표농도주입의 Regimen 아주대하교 대학원 의학과 이 인 경 (지도교수 : 이영주) 연구 목적 : 본 연구는 remifentanil 의 목표농도주입시 중심효과처 농도를 여러 가지 regimen 으로 단계적으로 증가시켰을 때 remifentanil 유발 기침을 예방하는데 효과적인지 알아보고자 하였다. 연구 방법 : 이전 연구에서 140 명의 환자들을 무작위로 2 군으로 나누었다. 두 군 모두 2 단계의 중심 효과처 목표 농도 증가를 이용하여 remifentanil 을 투여받았는데, 한 군은 1.0 에서 4.0ng/ml 로, 한 군은 2.0 에서 4.0ng/ml 로 증가시켰다. 이 연구 결과를 바탕으로 본 연구에서는 3 단계의 목표농도주입을 시행하였고(1.0 에서 2.0, 그리고 4.0ng/ml), 처음부터 4.0ng/ml 로 즉시 목표농도주입을 시작한 군과 비교하기 위해 새로운 140 명의 환자를 무작위로 두 군으로 나누어 연구를 진행하였다. 기침이 발생했을 경우를 기록하였고, 그 정도를 약함(1-2), 중간(3-4), 심함(5 회 이상)으로 분류하여 기록하였다. 결과 : R1-4 군의 1 명(1.5%)의 환자가 1 단계에서 기침을 하였으며, 5 명(7.3%)의 환자가 2 단계에서 기침을 하였다. R2-4 군에서는 9 명(13.2%)의 환자가 1 단계에서 기침을 하였고, 2 단계에서는 기침을 하는 환자가 없었다. 1 명의 환자만이 R1-2-4 군의 3 단계 목표농도주입시에 기침을 하였고, 이는

R4 군에 비교하였을 때 기침의 발생율과 정도에서 통계적으로 유의하게 감소된

결과를 보였다. (P < 0.001)

결론 : Remifentanil 의 목표농도주입시 단계적 증량은 remifentanil 유발 기침의 발생율을 줄여주고, 특히 3 단계 증량 시에는 거의 발생하지 않았다.

Key words: Remifentanil, Cough, Target-controlled infusion, Opioid.