morphine with adjuvant ketamine vs. higher …library.tasmc.org.il/ · induction of the...

DOI 10.1378/chest.08-0246 published online August 27, 2008; Chest

Shoshana Chazan and Avi A. Weinbroum Nachum Nesher, Margaret P. Ekstein, Yoseph Paz, Nissim Marouani,

ANALGESIAIMMEDIATE POST-THORACOTOMYHIGHER DOSES OF MORPHINE ALONE FOR MORPHINE WITH ADJUVANT KETAMINE VS.

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1

MORPHINE WITH ADJUVANT KETAMINE VS. HIGHER DOSES OF MORPHINE 1

ALONE FOR IMMEDIATE POST-THORACOTOMY ANALGESIA 2

3

Nachum Nesher, MD,1 Margaret P. Ekstein, MD,2 Yoseph Paz, MD,3 Nissim Marouani, 4

MD,4 Shoshana Chazan, RN,5 and Avi A. Weinbroum, MD6 5

1Department of Cardiothoracic Surgery, email: [email protected] 6

2Department of Anesthesia and Intensive Care Medicine, email: 7

[email protected] 8

3Department of Cardiothoracic Surgery, email: [email protected] 9

4Acute Pain Service Department of Anesthesia and Intensive Care Medicine, email: 10

[email protected] 11

5Acute Pain Service Department of Anesthesia and Intensive Care Medicine, email: 12

[email protected] 13

6Chief Post-Anesthesia Care Unit, Professor Department of Anesthesia and Intensive Care 14

Medicine, email: [email protected] 15

Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, 16

Tel Aviv, Israel. 17

18

Corresponding author: Avi A. Weinbroum, MD 19

Professor of Anesthesiology and CCM 20

Director, Post-Anesthesia Care Unit 21

Tel Aviv Sourasky Medical Center 22

6 Weizman Street, Tel Aviv 64239, Israel 23

Tel: 972-3-6973237; Fax 972-3-6925749 24

E-mail: [email protected] 25

Abstract: 267 wordsArticle: 2676 words

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2

Parts of this study were presented at the Euroanaesthesia 2003 Meeting, Glasgow, Scotland 26

and at the 5th International Congress on Coronary Artery Disease, 2003, Florence, Italy. 27

No financial support was received for this clinical trial. 28

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ABSTRACT 29

Background: Thoracotomy is associated with severe pain. We hypothesized that the 30

concomitant use of a subanesthetic dose of ketamine plus a ⅔-standard morphine dose might 31

provide more effective analgesia with fewer side effects than a standard morphine dose for 32

early pain control. 33

Methods: We conducted a 6-month randomized, double blind study in patients undergoing 34

thoracotomy for minimally invasive direct coronary artery bypass or for lung tumor resection. 35

After extubation, when objectively awake (≥5/10 VAS) and complaining of pain (≥5/10 36

VAS), patients were connected to a PCIA delivering 1.5mg morphine/bolus (MO group) or 37

1.0mg morphine+5mg ketamine/bolus (MK group), with a 7-minute lockout time. Rescue 38

intramuscular diclofenac 75mg was available. Follow-up lasted 4h. 39

Results: Forty-one patients completed the study. MO patients (n=20) used 6.8±1.9 40

(mean±SD) and 5.5±3.6 mg/h morphine during h 1 and 2, respectively; MK patients (n=21) 41

used 3.7±1.2 and 2.8±2.3 mg/h, respectively (P<0.01). The 4-h activation rate of the device 42

was double in the MOs than the MKs (66 ± 54 vs. 28 ± 20, P<0.001). The maximal self- 43

rated pain score was 5.6±1.0 for the MO vs. 3.7±0.7 for the MK group (P<0.01). Four MO 44

patients vs. one MK required diclofenac; 6 MO but no MK patients had SpO2 <94% on a 45

FiO2=0.4 (P<0.01); two MO patients required re-intubation. PaCO2 was higher in the MO 46

group (40±6 vs. 33±5 mmHg, P<0.05). Heart rate, blood pressure and incidence of 47

nausea/vomiting were similar; no ketamine-related hallucinations were detected. 48

Conclusions: Subanesthetic ketamine combined with a 35%-lower morphine dose provided 49

equivalent pain control compared to the standard morphine dose alone, with fewer adverse 50

side effects and a 45%-reduction in morphine consumption. 51

52

Registered at this site ClinicalTrials.gov; Registration number NCT00625911 53

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KEY WORDS: thoracotomy, analgesia, minimally invasive direct coronary artery bypass 54

(MIDCAB), lung tumor, pain, postoperative, morphine, ketamine 55

56

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ABBREVIATION LIST 57

ANOVA, analysis of variance 58

ASA, American Society of Anesthesiologists 59

BMI, body mass index 60

CICU, cardiac intensive care unit 61

EF, ejection fraction 62

FEV1/FVC, forced expiratory volume (in one second)/forced vital capacity 63

FiO2, fraction of inspired oxygen 64

IQR, inter-quarterly ratio 65

IV, intravenous 66

MIDCAB, minimally invasive direct coronary artery bypass 67

MK group, morphine 1.0 mg + 5 mg ketamine /bolus 68

MO group, morphine 1.5 mg/bolus 69

NMDA, N-methyl-D-aspartate 70

NSAIDs, non-steroidal anti-inflammatory drugs 71

PaCO2, arterial blood partial pressure of carbon dioxide 72

PACU, post-anesthesia care unit 73

PCIA, patient-controlled intravenous analgesia 74

PONV, postoperative nausea and/or vomiting 75

SpO2, pulse-derived arterial blood oxygen saturation 76

VAS, visual analogue scale 77

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INTRODUCTION 78

Thoracotomy, whether performed for the resection of lung tumor or for minimally invasive 79

direct coronary artery bypass, MIDCAB, surgery, is associated with severe and sometimes 80

uncontrolled, debilitating pain.1,2 Catecholamine release in response to nociceptive stimuli3 is 81

associated with undesirable hemodynamic consequences as well as disturbances in 82

respiratory, endocrine, metabolic4 and immune function.5 These changes may increase the 83

rate of complications, prolong hospitalization and augment cost.4-6 Importantly, if the acute 84

pain is not effectively controlled, it may evolve into severe chronic pain.7 85

Postoperative pain that is uncontrollable despite the administration of considerable 86

amounts of IV morphine could suggest tolerance to the drug.8-10 The administration of large 87

amounts of morphine to the awakening patient may cause respiratory and hemodynamic 88

depression.11,12 These effects may be especially serious when they follow lung lobectomy2 or 89

when they occur in patients with poor left ventricular function.13,14 For these reasons, 90

supplementation of morphine with non-narcotics (adjuvant agents) may be a way of 91

effectively controlling pain while reducing the incidence of adverse events.15,16 92

Ketamine, a noncompetitive NMDA-receptor antagonist, was shown to enhance 93

opioid-induced antinociception,17 to reduce hyperalgesia and to prevent morphine-induced 94

resistance 18,19 and, when combined with morphine, to lower post operative morphine 95

consumption.20 Given that subanesthetic (≤500 mcg/kg) doses of ketamine seldom produce 96

undesired hemodynamic alterations (e.g., elevated heart rate and blood pressure),21 we 97

hypothesized that by combining a subanesthetic dose of ketamine with morphine, we could 98

effectively control pain, while reducing postoperative morphine demand and drowsiness, with 99

an acceptable level of adverse side effects. The primary end point was pain VAS that was 100

used to calculate the sample size (see statistical paragraph); the secondary parameters 101

measured were morphine consumption, PCA activation, and side effects. 102

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103

PATIENTS AND METHODS 104

After the Ethics Committee of the Tel-Aviv Sourasky Medical Center approved this study’s 105

protocol, 44 patients scheduled for elective MIDCAB or for lung resection via thoracotomy 106

during a 6-month period (September 2001- March 2002) were enrolled in the study. They all 107

gave their informed, written consent to participate in this double blind study and were 108

randomly assigned to one of two groups according to their national ID number. Patients were 109

eligible for the study if they had been referred for a first time isolated coronary bypass and if 110

their surgeon considered them candidates for a MIDCAB procedure, or if they were to 111

undergo lung surgery. Exclusion criteria were ASA physical class ≥3, emergency operations, 112

Q-wave myocardial infarct occurring during the previous 3 weeks, or poor left ventricular 113

function (e.g., EF <30% by echocardiography or angiography). Other exclusion criteria were: 114

a BMI >35 kg/m2, past or current neuropathy or psychological disturbances, the use of 115

psychiatric medications, including anti-depressants and anti-psychotic agents, chronic liver or 116

renal failure requiring dialysis, a FEV1/FVC <70%, allergy to ketamine, morphine or 117

NSAIDs, clotting abnormalities, a platelets count <70000/mm3, a white blood count 118

<3000>14000/mm3, uncontrolled diabetes mellitus or fasting blood glucose >250 g/dl, 119

evidence of sepsis or infection up to one week prior to randomization. There was no age 120

restriction. 121

Anesthesia protocol 122

General anesthesia was administrated by the same anesthetist and no regional block was used. 123

Induction of the standardized anesthesia consisted of IV midazolam 2 mg, propofol 1 mg/kg, 124

medium-dose fentanyl (5-15 mcg/kg) and pancuronium (0.1mg/kg) to facilitate endotracheal 125

intubation. Anesthesia was maintained by repeated doses of fentanyl and pancuronium when 126

deemed necessary. All patients were ventilated in a volume-controlled mode with a tidal 127

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volume of 6 ml/kg and received oxygen enriched with isoflurane (0.4-0.8% inspired 128

concentration). Neuromuscular relaxation was reversed pharmacologically at the end of 129

surgery. When the patients resumed spontaneous respiration, responded adequately to orders 130

and demonstrated negative inspiratory force of at least 20 cmH2O or vital capacity greater 131

than 20cc/kg, their tracheas were extubated. Patients who were not extubated in the operating 132

room were excluded from the study (see “allocation” boxes in CONSORT Statement, Fig. 1). 133

The postoperative monitoring included the measurements of heart rate by a 5-lead 134

electrocardiograph, invasive systolic and diastolic blood pressures, respiratory rate, and SpO2, 135

(AS/3™, Datex-Ohmeda®, Helsinki, Finland). 136

Postoperative analgesia protocol 137

All patients were transferred to the PACU where postoperative follow-up started. They 138

received IV analgesics (per patient request) starting from when their pain was score was 139

≥5/10 on a 0-10 VAS, see below) and when the attending physician determined that the 140

patient was in an acceptable cognitive state (≥5/10 VAS). A cutoff pain score was chosen on 141

the basis of previous experience in acute pain control.2,13 Drug injections consisted of either 142

1.5 mg morphine plus saline (group MO) or 1 mg morphine plus 5 mg ketamine (group MK). 143

A blinded anesthesiologist prepared the separate syringes based on the randomization list and 144

administered the first dose, after which the PCIA device was turned on. The device was 145

preset to deliver similar boluses whenever the patient activated it, controlled by a 7-minute 146

lockout period. If the protocol was ineffective to reduce pain VAS by ≥2 levels or patients 147

reported no satisfaction of the treatment within 30 minutes of treatment, a rescue dose of 148

intramuscular diclofenac 75 mg was available by the nurses. 149

One of two designated PACU nurses, who were blinded to the drug assignment, 150

assessed the variables listed below for each patient during the entire stay in the PACU. VAS 151

scores were assessed every 15 minutes: 152

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• Subjective pain intensity was patient self-rated, based on a VAS graded from “no 153

pain”=0 to “worst possible pain”=10. 154

• A patient’s subjective level of wakefulness was assessed by a self-rated VAS, from 155

1=heavily sedated to 10=fully awake. If patients were asleep, they were awakened to 156

obtain their rating; the data of patients unable to cooperate were excluded at that time 157

point. 158

• An SpO2-derived value of 94%, with 40% oxygen by facemask, was the lowest limit 159

allowed for arterial oxygenation, otherwise a 100% oxygen mask was placed and the 160

various patient's data from that time point were not recorded. 161

• Untoward effects (e. g., nausea, vomiting or any distress) were recorded by the nurse 162

and treated as indicated (e. g., metoclopramide 10 mg IV for nausea or vomiting). 163

Nurses specifically asked patients if hallucinations occurred and reported them. 164

Reintubation in the psotoeprative period, if necessary, was decided by the blinded PACU 165

attending physician based on clinical and laboratory data. 166

Patients were kept for 4 h in the PACU and then were transferred to the CICU for further 167

observation; no further data were collected thereafter. 168

Statistical analysis 169

The analyses were performed at the Statistical Laboratory of the School of Mathematics, Tel- 170

Aviv University, using the SPSS Release for Windows, Version 11.01 (Chicago, IL, 2002). A 171

pre-study power table where delta (representing the mean difference in pain score recorded in 172

a pilot study)=2.1, alpha=0.05 and power=0.97 resulted in the need for a minimum of 15 173

patients in each group. The demographic data (age, weight) and background characteristics 174

(baseline heart and respiratory rates, SpO2, systolic and diastolic blood pressures), the ASA 175

physical class, duration of surgery and intraoperative drug dosages, as well as fluid and blood 176

administration, were compared using one-way analysis of variance (ANOVA). Patients’ 177

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gender and intra-group procedure distributions were analyzed using the Fisher exact test. The 178

rates of the hourly demands of the PCIA devices were square rooted in order to obtain their 179

normal distribution; the results were then analyzed by one-way ANOVA with repeated 180

measures. The number of times the patients received a rescue drug and the rate of side effects 181

were also analyzed using the Fisher exact test. The effects of type of analgesia on the 182

patients’ self-rated pain and grade of wakefulness (VAS's), as well as the hourly amounts of 183

analgesic use were also analyzed using the ANOVA with repeated measures. The ANOVA 184

tests were always followed by the post-hoc Tukey’s Honest Significant Difference method. 185

All values are expressed as mean ± standard deviation (SD), with significance defined as 186

P≤0.05. 187

188

RESULTS 189

Out of 62 screened patients, 44 fulfilled the study criteria for randomization. Three of them 190

subsequently dropped out after surgery because they required continuous ventilation 191

(CONSORT statement, Fig. 1); no MIDCAB patient was converted to an on-pump procedure. 192

The demographic, anesthesia and surgical data were similar between the two drug study 193

groups (Table 1); intraoperative blood replacement and fluid infusion were similar as well 194

(data not shown). Baseline (immediately before starting study drug administration) vital 195

signs, patients’ self-rated pain intensity (Fig. 2) and wakefulness scores (data not shown) 196

were also similar between the groups. 197

Overall, the amounts of analgesics that were requested by the patients to alleviate pain 198

were found to be associated with the drug regimen. The MK group required 45% of the total 199

amount of morphine used by the MO group (P<0.001), ranges being 16-19 mg/4h, and 200

applied the PCIA more frequently (66 ± 54 vs. 28 ± 20, P<0.001, Fig. 3). The MO group 201

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requested more diclofenac per the protocol (P=NS) than the MK group (Table 1); in all cases 202

the rescue treatment was effective. 203

The subjectively evaluated pain intensity (VAS) during the 4-h PACU stay was 204

significantly (P<0.001) lower for the MK group compared to their MO counterparts (Fig. 2), 205

despite the larger amount of morphine that had been administered to the latter group. The 206

subjectively rated wakefulness scores for the MK group were also better (p<0.05) than those 207

for the MO group (Table 1). 208

All the recorded respiratory parameters were better in the MK group compared to the 209

MO group (Table 1): none of the MK patients had an SpO2 <94% with 40% oxygen by 210

facemask, but 6 of the MO patients did at one time point each (P<0.01): SpO2 values 211

improved better in the former than in the latter (Table 1) and PaCO2 were also lower in the 212

former. Two of the latter group subsequently required re-intubation and mechanical 213

ventilation for a period of 5-6 hours due to clinical respiratory distress associated with an 214

increase in heart rate and systolic blood pressure. The mean 4-h-respiratory rate was also 215

better in the MK group than in the MO group (Table 1). Finally, 1 h after the drugs were first 216

injected, heart rate and blood pressures in both groups decreased and stabilized for the rest of 217

the study period: interestingly, they were almost identical in both study groups (Fig. 4). 218

The incidence of PONV was similar between the groups (Table 1); all incidents were 219

short-lived and responded well to appropriate therapy. One MK patient reported a sensation 220

of lightheadedness that resolved spontaneously in <4 minutes, and at no time did any patients 221

report hallucinations or postoperative confusion. 222

None of the study patients in either group were kept in the PACU for more than the 223

protocol dictated period and all were transferred to the ward after fulfilling PACU discharge 224

criteria. All the study patients were later discharged from the CICU uneventfully according to 225

the cardiothoracic departmental discharge policies. 226

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227

DISCUSSION 228

Our study demonstrates that the administration of an IV subanesthetic dose (5 mg/bolus) of 229

ketamine combined with ⅔ of the standard (1.5 mg) morphine dose provided lower subjective 230

measures of pain (by >2 points on a scale of 1-10) than the standard morphine dose alone 231

during the immediate (4 h) post-thoracotomy period. The combined protocol was also 232

associated with remarkably stable hemodynamic conditions and better respiratory parameters 233

than the MO group. These objective effects were associated with a better self-rated level of 234

wakefulness, similar PONV, and insignificant ketamine specific side effects. 235

Postoperative pain ranks among the major problems of surgical patients, especially 236

after thoracotomy.2,22 During the last few years, evaluation of intense pain associated with 237

thoracotomy has become a subject of considerable interest, since both lung resection and 238

MIDCAB share the properties of newly evolving minimally invasive and “fast-tracking” 239

surgical techniques.23 240

Ketamine hydrochloride is a well known general dissociative anesthetic and a short 241

acting analgesic with antagonist activity at the NMDA receptor. Morphine and other opioids 242

produce antinociception via mu receptor agonistic activity and by the activation of the 243

monoaminergic descending pathways at the spinal level,10 they also activate the NMDA 244

receptor, resulting in hyperalgesia and development of tolerance to opioids.3,10 If tolerance is 245

one of the explanations for severe postoperative pain small doses of ketamine added to 246

morphine could treat pain better than morphine alone.8,10 247

If given alone, ketamine in small doses (<250 mcg/kg IV) may seldom induce a 248

change in level of consciousness lasting a few minutes because of the large plasma 249

concentration that develops immediately after the injection.24 Whereas the plasma half-life of 250

ketamine is only 15-20 minutes, the analgesic effect of the MK combination was evident and 251

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clinically stable throughout the 4-h observation period. The drug combination dose that was 252

used in this study allowed for a prompt reduction of pain and a morphine sparing effect. 253

These current results are supported by our previous data25 that demonstrated the beneficial 254

combination of ketamine and morphine in patients suffering from severe postoperative pain 255

that was resistant to morphine. 256

Heart rate and blood pressure are negatively affected by large morphine doses given 257

within a short period of time, but most importantly, respiratory rate, oxygenation and 258

adequate ventilation may drastically worsen because of the increased sedation.4,12 We 259

observed such events in several individuals in the MO group. On the other hand, the ketamine 260

dose of anesthesia is known to increase heart rate and blood pressure due to its pro-adrenergic 261

effect: our MK patients did not exhibit these reactions, either because of the very low 262

ketamine dose and/or because of its combination with morphine. The evidence of almost 263

identical pulse rates and blood pressures in both groups is, therefore, promising, especially in 264

the MIDCAB subgroup of patients of this study. 265

Reducing postoperative pain enhances the ability to breathe deeply and cough 266

effectively. All these features lead to better oxygenation and a probable preservation of 267

positive myocardial oxygen balance. 268

Ketamine alone may produce drowsiness;21,26 our MK patients, however, self-rated 269

themselves more awake than their MO counterparts, supporting the findings of an earlier 270

report.25 Short lived hallucinations are the most frequently mentioned side effect of ketamine, 271

especially if administered at doses ≥500 mcg/kg.27,28 Some reports indicated that up to 30% 272

of the patients receiving IV anesthesia doses of ketamine (0.5-1.5 mg/kg) experienced 273

unpleasant dreams or acute psychosis-like symptoms.29 In our current MK study group, there 274

were no reports of hallucinations or bad dreams, a finding we consider to be due to the small 275

intermittent dosage.25 276

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This study is limited by the short duration of follow up. The results of this study 277

cannot be extrapolated to imply that improving pain for the initial 4 postoperative h has long- 278

term effects on pain control or overall recovery. Nevertheless, effective initial pain control is 279

an important factor among other determinants of safe recovery and patient satisfaction. Also, 280

the specific cohort of coronary bypass patients presented here was managed with the "fast 281

track" mode of immediate awakening and extubation, the success of this approach is 282

dependent, among other things, on level of pain, wakefulness and adequate pulmonary 283

function. Indeed, the ketamine+morphine group fared significantly better in all of these 284

parameters. Another limitation is the theoretical difference between the incisions used for the 285

MIDCAB vs. the lung lobectomy. MIDCAB’s were performed via an anterolateral incision, 286

with the patients lying in the supine position, whereas lung resections were performed via a 287

more lateral incision, with the patients positioned more laterally. However, both types of 288

incision were similarly represented in both study groups. One other potential limitation to the 289

analysis of our data is the possibility of inter-observer variability between the PACU nurses 290

who collected the data. To minimize variability, there were only 2 dedicated nurses in the 291

PACU who assumed responsibility for the study patients. 292

In conclusion, immediate (4 h) postoperative subanesthetic doses of ketamine added 293

to ⅔ the standard dose of morphine provided equivalent analgesia with a better safety profile 294

compared to that obtained by a standard dose of morphine alone, in patients undergoing 295

thoracotomy for lung tumor resection or MIDCAB. The MK patients were hemodynamically 296

stable and there were signs of less respiratory depression compared to the MO group. MK 297

patients self-rated their wakefulness as being better than the MO patients. We recommend 298

additional studies to confirm our findings so that this promising drug protocol can be 299

considered safe for use in postoperative pain control of pulmonary and cardiac patients. 300

301

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Acknowledgment: The authors thank Esther Eshkol, MA (institutional medical copyeditor, 302

Tel Aviv Sourasky Medical Center) for editorial assistance, and the nursing staff of the 303

PACU for their collaboration and dedication. 304

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Table 1. Demographic, intraoperative and 4h-postoperative data (mean ± SD or absolute 375

numbers). 376

Parameter Morphine

(n=20)

Morphine+Ketamine

(n=21)

P-values

Age (years)* 58 ± 12 61 ± 11 0.41

Weight (kg)* 73 ± 8 76 ± 14 0.4

Male/Female* 13/9 10/12 0.16

MIDCAB/lung surgery (n)* 7/15 6/16 0.25

Duration of surgery (h)* 3.1 ± 1.3 3.5 ± 1.0 0.28

MO 1st-h consumption (mg) 6.8 ± 1.9 3.7 ± 1.2 0.0001

MO 2nd-h consumption (mg) 5.5 ± 3.6 2.8 ± 2.3 0.008

Diclofenac consumption (n) 4 1 0.14

Maximal pain (VAS 0-10)** 5.6 ± 1.0 3.7 ± 0.7 0.0001

90-min arterial blood pCO2 (mm Hg) 40 ± 6 33 ± 5 0.0003

SpO2 changes over 90min (%)*** 1.0±1.0 4.5±1.0 0.0001

Respiratory rate (breaths/minute) 19 ± 1 13 ± 1 0.0001

Wakefulness score (VAS 1-10) 1.2 ±3.2 1.2±5.5 0.0001

Incidence of PONV (n) 3 1 0.24

*Including data of the excluded (2 MO and 1 MK) patients; statistical analyses followed the 377

intent-to-analyze format. **Collected before patient's discharge. ***Difference between 378

baseline and 90-min values. 379

Page 19 of 24



20

Figure legends. 380

Fig. 1. CONSORT statement of the study. 381

382

Fig. 2. Four-hour pain trends (mean ± SD). 383

VAS, visual analogue scale. 384

*P<0.001 (by ANOVA with repeated measures). 385

386

Fig. 3. Square-rooted number of PCIA device applications (median and IQR). 387

*P<0.0001 (by ANOVA with repeated measures). 388

389

Fig. 4. Four-hour hemodynamics (systolic and diastolic blood pressures and heart rate) (mean 390

± SD). 391

392

Page 20 of 24



Excluded (n=0)

Not meetingInclusionCriteria (n=0)

Refused to Participate (n=0)

Other reasons(n=0)

Assessed forEligibility (n=44)

Randomized (n=44)

Allocated to MO (n=22)

Received allocated Intervention (n=20)

Did not receive Allocated Intervention(n=2, due topostoperativemechanical ventilation)

Allocated to MK (n=22)

Received allocated Intervention (n=21)

Did not receive Allocated Intervention:(n=1, due to postoperative mechanical ventilation)

Lost to follow-up (n=0)

Discontinued Intervention (n=0)

Conversion (n=0)

Lost to follow-up (n=0)

Discontinued Intervention (n=0)

Conversion (n=0)

Analyzed (n=20)

Excluded fromAnalysis (n=2)

Dropped out (n=0)

Analyzed (n=21)

Excluded fromAnalysis (n=1)

Dropped out (n=0)

Ana

lysi

sF

ollo

w-u

pA

lloca

tion

Enr

olm

ent

Fig. 1. Flow diagram of the progress through the phases of the randomized trial

Page 21 of 24



1

Fig. 2. 1

0 15 30 45 60 75 90 105 120 135 150 165 180 195 210 225 240

0

1

2

3

4

5

6

7

8

9

10

*

Morphine (MO)Morphine+Ketamine (MK)

Pai

nV

AS

(0-1

0)

Time (min) of observation

2

Page 22 of 24



Fig. 3.

0

2

4

6

8

10

12

14

16

MO PatientsMK Patients

*

Squ

are-

Roo

ted

Num

ber

of D

evic

e A

pplic

atio

ns

Study Groups

Page 23 of 24



1

Fig. 4. 1

2

0 60 120 240

60

80

100

120

140

160

180

15 30

SBP-MO SBP-MK DBP-MO DBP-MK HR-MO HR-MK

Blo

od p

ress

ures

(m

mH

g)or

hea

rt r

ate

(bpm

)

Time (min) of observation

3

4

Page 24 of 24



DOI 10.1378/chest.08-0246 published online August 27, 2008; Chest

Chazan and Avi A. Weinbroum Nachum Nesher, Margaret P. Ekstein, Yoseph Paz, Nissim Marouani, Shoshana

MORPHINE ALONE FOR IMMEDIATE POST-THORACOTOMY ANALGESIAMORPHINE WITH ADJUVANT KETAMINE VS. HIGHER DOSES OF

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