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The effect of dexmedetomidine on agitation during weaning of mechanical ventilation in critically ill patients.

Mechanically ventilated patients frequently require sedation and analgesia to reduce anxiety and discomfort from endotracheal tubes and to facilitate other intensive care unit (ICU) procedures (1). When mechanical ventilation is no longer required and sedation is weaned, patients can often develop agitation and/or delirium. In mechanically ventilated patients, the incidence of severe agitation has been reported at between 16 (2) and 29% (3). In the ICU setting, severe agitation can lead to traumatic self-extubation, extended duration of opioid and benzodiazepine treatment, longer length of stay and prolonged mechanical ventilation (2). Longer-term effects can include prolonged cognitive dysfunction and increased risk of post-traumatic stress disorder. At six months post-discharge, post-traumatic stress disorder was present in 14% of patients who had been mechanically ventilated in an ICU (4).

Current evidence-based guidelines for weaning and discontinuing ventilatory support (5) identified non-respiratory causes and, in particular, psychological factors such as fear, anxiety, agitation and pain as the most important non-respiratory factors to consider during liberation from ventilatory support. A systematic review identified the paucity of trials of interventions to facilitate weaning from mechanical ventilation and called for more research into the non-pulmonary causes of weaning failure (6).

The 2002 clinical practice guidelines for sedation and analgesia in the critically ill (7) recommends the use of midazolam, diazepam, propofol or lorazepam for sedation of agitated ICU patients, and haloperidol as the agent of choice for delirium. However, the efficacy and safety profiles of these agents in this particular group of patients are not established (7-10). Furthermore, different approaches have also been implemented to reduce oversedation, including a nurse-directed protocol (11) and daily interruption of sedation (12) with reduction in ventilation time and intensive care length of stay.

A recent review (13) called for a systematic approach to implement a strategy to optimise analgesia and sedation in the critically ill. Such a strategy would focus on effective pain relief and include protocolised monitored sedation and co-ordinated care in an effort to alleviate problems inherited with conventional sedatives and analgesics.

An ideal agent for the ICU would provide effective pain control and sedation with a rapid onset of action, resulting in a calm patient who can be easily aroused for assessment. It should also allow for rapid recovery after discontinuation, with minimal systemic accumulation and an acceptable safety profile (14).

Dexmedetomidine is a highly selective alpha-2 agonist, producing sedation and anxiolysis due to a reduction in sympathetic central nervous system activity. A major advantage over other recommended sedatives is that it is associated with minimal respiratory depression (15), an important consideration when patients are ready to wean from mechanical ventilation. Moreover, its activation of alpha-2 receptors accentuates the action of opioids, reducing the doses needed to achieve adequate pain relief (14). These analgesic and sedative effects make dexmedetomidine an attractive agent in the weaning of agitated ICU patients.

The aim of this prospective study was to evaluate the effects of dexmedetomidine on resolution of agitation during weaning from mechanical ventilation of critically ill patients who failed conventional therapy.

MATERIALS AND METHODS

Study type and site

This was a prospective, open-label, observational cohort study. It was performed in tertiary medical/ surgical intensive care units at the Prince of Wales Hospital (a principal teaching hospital of the University of New South Wales) and the collocated Prince of Wales Private Hospital in Sydney, New South Wales. The South East Sydney Area Health Service Ethics Committee approved the study. Written informed consent was obtained from the person responsible prior to enrolment in the study. Furthermore, approval was obtained (Clinical Trial Notification Scheme) for the use of dexmedetomidine up to a dose of 1.0 [micro]g/kg/hour and for longer than 24 hours--both higher than the current registered licence in Australia.

Patients

Inclusion criteria were: aged over 18 years, requiring invasive mechanical ventilation for longer than 24 hours, sedatives and/or opioids for longer than 24 hours, development of clinical agitation and/or delirium upon weaning from sedation and/or opioids and failure to achieve successful extubation with conventional therapy and weaning as assessed by the treating intensivist. In the ICUs included in this study, conventional first-line treatment for agitation consists of intravenous midazolam and/or propofol infusions, with the addition of intravenous haloperidol boluses as required. Nasogastric alprazolam is added if further anxiolytic therapy is required. Exclusion criteria were: allergy to dexmedetomidine, pregnancy or lactation, systolic blood pressure <90 mmHg and/or heart rate <55 beats per minute, likely to die within 24 hours and/or likely withdrawal of therapy, long-term [alpha]-2 agonist prescription, known opiate or benzodiazepine dependence or treatment for chronic pain or detoxification therapy within the preceding six months, chronic antipsychotic drug prescription, dementia, parkinsonism or chronic epilepsy, recent cerebrovascular surgery or severe traumatic brain injury, recent surgery involving a free arterial flap, hepatic encephalopathy within the last 14 days, recent drug overdose or carbon monoxide poisoning.

Ventilation strategy

Intubated patients were ventilated via pressure support ventilation and positive end-expiratory pressure with a low synchronised intermittent mandatory ventilation rate within 24 hours of intubation. Patients were considered for extubation after resolution of primary pathology when their fractional inspired oxygen (Fi[O.sub.2]) was <0.40 achieving a partial pressure of arterial oxygen ([P.sub.a][O.sub.2]) >70 mmHg, pressure support ventilation and positive end-expiratory pressure [less than or equal to]10 cm[H.sub.2]O, and spontaneous tidal volume >5 ml/kg with a frequency of <30 /minute. Patients should have been within a Motor Activity Assessment Scale (MAAS) range of 2 to 4.

Intervention

While several instruments for assessing sedation and agitation have been validated, there is no accepted 'gold standard' scale. At our institution, the MAAS (16) was the current practice tool, the staff were familiar with its use and it was thus utilised for sedation assessment.

Conventional therapy was running for up to 48 hours prior to enrolment. Dexmedetomidine infusion without a loading dose was commenced at 0.4 [micro]g/kg/hour for two hours, after which it was titrated by 0.2 [micro]g/kg/hour every 30 minutes up to a maximum dose of 1 [micro]g/kg/hour, to obtain a target MAAS score of 2 to 4 ('responsive to touch or name', 'calm and co-operative' or 'restless but co-operative'). Concurrent sedative and/ or opioid therapy was preferentially weaned two hours after initiating dexmedetomidine infusion. Rescue sedation (midazolam 1 mg and/or propofol) was given for MAAS scores of 5 to 6. Additional analgesia (morphine 1 to 2 mg or fentanyl 10 to 20 [micro]g) was given if required. MAAS scores were re-evaluated at six and 12 hours and ventilator weaning continued as clinically appropriate. Dexmedetomidine infusion was discontinued once no longer required, at the discretion of the treating intensivist or when 14 days of dexmedetomidine infusion were completed.

Outcome measures

The main outcome was the percentage of patients achieving target MAAS score (2 to 4) assessed at six and 12 hours following the commencement of dexmedetomidine infusion. Other outcome measures included hours of ventilation, number of patients extubated and additional sedatives and analgesia after initiation of dexmedetomidine infusion.

Ventilation time included time of artificial airway such as tracheostomy tube. Successful extubation was documented when no re-intubation occurred within 48 hours.

Statistical analysis

Percentage and median were calculated for categorical and continuous variables, respectively. Interquartile range (IQR) was calculated for continuous variables. Fisher's exact test was used to compare the proportion of patients in the target MAAS category at baseline (zero hours) and at six and 12 hours after commencement of dexmedetomidine infusion. A P value of <0.05 was considered statistically significant and all analyses were done using Stata 9.2 software.

RESULTS

Twenty-eight patients were enrolled, with a total of 30 episodes recorded. Patients were ventilated for a median (IQR) ventilation time of 115 (87 to 263) hours before enrolment. These patients represented a group with complex and difficult clinical conditions complicated by agitation and failure to liberate from mechanical ventilation. Details of the individual patients' characteristics, including admission diagnosis, co-morbidities and pre-enrolment conventional sedation, are outlined in Table 1. It should be noted that some patients had their sedative medications significantly reduced during the 48 hours prior to enrolment due to over-sedation; therefore, the amount of sedation documented may underestimate the true sedation requirements prior to dexmedetomidine infusion.

Immediately prior to dexmedetomidine infusion, 23 (77%) episodes were outside the target MAAS range with seven episodes (23%) within target range, where agitation developed upon sedative withdrawal in preparation for extubation. The number of agitation episodes decreased from 23 (77%) at enrolment to four (13%) by 12 hours (P <0.001). Within six hours after commencement of dexmedetomidine infusion, 28 episodes (93%) were at target sedation level (P <0.001) and this benefit was maintained at 12 hours (26 episodes or 87%, P <0.001; Figure 1). There was no significant difference between the proportion of patients at target sedation level at six and 12 hours post commencement of the dexmedetomidine infusion (P=0.671).

The majority of patients were males with a median age of 70 years. The cohort clinical characteristics including vasopressor requirement and hospital outcome are presented in Table 2. At the commencement of dexmedetomidine infusion, 10 patients (33%) were on noradrenaline or adrenaline and nine (30%) were on dobutamine.

The median maximum dexmedetomidine dose was 0.7 [micro]g/kg/h (range 0.4 to 1.0) with a median infusion time of 62 hours (range 24 to 252). Most patients (72%) required no or low-dose additional sedatives within 48 hours of study infusion. Excluding unrelated clinical deterioration (detailed below), 22 episodes (73.3%) achieved successful weaning from ventilation (extubation). Details of dexmedetomidine infusion and ventilation related outcomes are shown in Table 3.

In 15 episodes (50%) sedation with dexmedetomidine was ceased as planned (Table 3). Of the remaining episodes, sedation with dexmedetomidine was discontinued in six patients (20%; patients 3, 10 to 13, 22; Table 1) due to significant unrelated clinical deterioration. Three of these patients experienced severe respiratory failure.

Adverse events recorded included one episode of self-extubation, lack of efficacy (13%) at the dose given, one episode of haemodynamic instability that resulted from sepsis requiring surgery and one episode requiring a moderate increase of noradrenaline and dobutamine dosage at 12 hours. Otherwise, there was no observed increase in vasopressor requirements within 12 hours of the infusion and one episode of elevated liver enzymes.

DISCUSSION

This study demonstrated the feasibility of using dexmedetomidine to facilitate weaning from mechanical ventilation in a group of complex critically ill patients after failure of conventional management. Dexmedetomidine produced rapid resolution of agitation and was effective in facilitating weaning from conventional sedation. Within six hours of dexmedetomidine treatment, MAAS scores were converted to mildly agitated or calm with target MAAS maintained at 12 hours (P <0.001) in most treatment episodes. This allowed successful weaning and extubation in more than half of the patients, and in 75% of episodes excluding those with unrelated clinical deterioration.

The majority of studies of dexmedetomidine in adult ICU patients have involved postoperative surgical cases (17-25). However, a recent randomised multicentre trial of 375 mostly medical ICU patients who were ventilated for more than 24 hours demonstrated that dexmedetomidine is safe and effective when compared to midazolam and used at doses up to 1.4 [micro]g/kg/hour and for up to 30 days. It also showed a significant reduction in delirium and a shorter ventilation time with dexmedetomidine treatment (26).

However, dexmedetomidine failed to facilitate the weaning process or control agitation at the prescribed dose in 13% of episodes. This highlights the need for a multimodal approach to sedation and analgesia in complex critically ill patients where no single agent can be adequate. It is not clear whether using a higher dose of dexmedetomidine would have resulted in a different outcome. One report found dexmedetomidine was no better than propofol in managing mechanically ventilated patients (17), while another reported enhanced agitation, severe pain and haemodynamic compromise associated with dexmedetomidine therapy (20). It is important to note that the maximum dose of dexmedetomidine used in the latter study by MacLaren et al was 0.54 [micro]g/kg/hour, which is much lower than the 1.0 [micro]g/kg/hour applied in our study. It is possible that the early weaning of concurrent sedatives (85% of their patients had ceased propofol at six hours and 61% had ceased lorazepam at six hours) combined with a low maximum dose of dexmedetomidine in this study may have contributed to this result. In a small UK phase II study to evaluate the efficacy of dexmedetomidine for sedation in a medical ICU, Venn et al reported that higher dexmedetomidine doses are required to sedate critically ill medical ICU patients than those typically used in post-surgical patients (27). These reports and our data suggest a dose-related response when using dexmedetomidine for agitated patients. Interestingly, a recent study found even low-dose dexmedetomidine infusion (0.05 to 0.4 [micro]g/kg/hour) to be effective in managing emergence delirium and agitation in Japanese patients, however half received epidural opioids for pain relief and less than half were ventilated (28).

There are few studies exploring the use of dexmedetomidine for agitation or delirium in mechanically ventilated, adult, medical ICU patients (28,29), and even fewer in patients weaning from sedation (20,22). Dexmedetomidine has been used to successfully facilitate the withdrawal of ventilation in trauma/surgical ICU patients who had failed weaning attempts because of agitation (22). The authors concluded that dexmedetomidine facilitated extubation by maintaining adequate sedation without haemodynamic instability or respiratory depression. It is likely that higher dexmedetomidine doses than the currently approved Australian maximum (31) of 0.7 [micro]g/kg/hour are needed to effectively manage agitation and sedation requirements in the medical ICU patient population. Data are accumulating regarding the safety profile of dexmedetomidine infusions lasting longer than 24 hours, suggesting that longer durations may be used safely26. In order to ensure the safe weaning of a number of the study patients it was necessary to run the dexmedetomidine infusion for up to 11 days, with a median of 2.5 days.

Although the exact mechanism by which dexmedetomidine counteracts agitation remains unclear, animal models show an increase in acetylcholine and reduction in noradrenaline levels in cerebrospinal fluid in response to dexmedetomidine, suggesting a central nervous system-mediated effect (32). High serum anticholinergic activity (low acetylcholine levels) is associated with delirium in elderly patients (33), and in our cohort the patients failing conventional treatment were considerably aged (Table 1). In addition, its synergistic effects with benzodiazepines and opioids may result in an overall reduction in sedative and opioid requirements (14).

Our study is limited by its observational nature, the small number of patients and the complex heterogeneous nature of the subjects' illnesses. However, it accurately reflected ICU clinical practice in that conventional therapy was at the discretion of the treating intensivist due to the lack of a 'gold standard' for management of agitated and/or delirious patients. We were unable to accuratey quantify the effect of dexmedetomidine on ventilation time and ICU length of stay due to prolonged ventilation and ICU stay during conventional weaning prior to dexmedetomidine therapy.

Despite these limitations, this study demonstrates that dexmedetomidine can be used successfully to treat emergence agitation in mechanically ventilated medical/surgical ICU patients undergoing weaning. This leads to the question of whether all agitated mechanically ventilated patients could benefit from the earlier use of dexmedetomidine to assist with weaning, rather than waiting until conventional treatment has failed. Such an approach has the potential to avoid extended ventilation times and increased ICU length of stay, but needs to be prospectively studied. Our study adds an important insight to the design of randomised trials to define the possible role of dexmedetomidine in managing agitation and/or delirium.

ACKNOWLEDGEMENTS

We thank the intensive care nursing staff for their contribution to this study and MediTech Media Pty Ltd for editorial assistance with manuscript preparation.

CONFLICT OF INTEREST

This study was an investigator-initiated study funded by the Prince of Wales Intensive Care Research Trust Fund. Currently, Dr Shehabi is Chair of the Sedation Advisory Board, supported by an educational grant from Hospira Australia and has received an honorarium for Board meetings. Dr Shehabi has no financial interest in Hospira Inc. shares or products. There is no conflict of interest to report with any of the co-authors.

Accepted for publication on June 4, 2009

REFERENCES

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(3.) Chanques G, Jaber S, Barbotte E, Violet S, Sebbane M, Perrigault P-F et al. Impact of systematic evaluation of pain and agitation in an intensive care unit. Crit Care Med 2006; 34:1691-1699.

(4.) Girard TD, Shintani AK, Jackson JC, Gordon SM, Pun BT, Henderson MS et al. Risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: a prospective cohort study. Crit Care 2007; 11:R28.

(5.) MacIntyre NR, Cook DJ, Ely EW Jr, Epstein SK, Fink JB, Heffner JE et al. Evidence-based guidelines for weaning and discontinuing ventilatory support: a collective task force facilitated by the American College of Chest Physicians; the American Association for Respiratory Care; and the American College of Critical Care Medicine. Chest 2001; 120:375S-95S.

(6.) Cook D, Meade M, Guyatt G, Butler R, Aldawood A, Epstein S. Trials of miscellaneous interventions to wean from mechanical ventilation. Chest 2001; 120:438S-444S.

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(8.) Arbour R. Propylene glycol toxicity occurs during low-dose infusions of lorazepam. Crit Care Med 2003; 31:664-665; author reply 665.

(9.) Caroff SN, Rosenberg H, Mann SC, Campbell EC, Sullivan KA. Neuroleptic malignant syndrome in the critical care unit. Crit Care Med 2002; 30:2609; author reply 2609-2610.

(10.) Price SR. Rotation of propofol and midazolam for long-term sedation. Crit Care Med 2004; 32:1435-1436; author reply 1436.

(11.) Brook AD, Ahrens TS, Schaiff R, Prentice D, Sherman G, Shannon W et al. Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation. Crit Care Med 1999; 27:2609-2615.

(12.) Kress JP, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342:1471-1477.

(13.) Schweickert WD, Kress JP. Strategies to optimize analgesia and sedation. Crit Care 2008; 12 (Suppl 3):S6.

(14.) Szumita PM, Baroletti SA, Anger KE, Wechsler ME. Sedation and analgesia in the intensive care unit: evaluating the role of dexmedetomidine. Am J Health Syst Pharm 2007; 64:37-44.

(15.) Venn RM, Hell J, Grounds RM. Respiratory effects of dexmedetomidine in the surgical patient requiring intensive care. Crit Care 2000; 4:302-308.

(16.) Devlin JW, Boleski G, Mlynarek M, Nerenz DR, Peterson E, Jankowski M et al. Motor Activity Assessment Scale: a valid and reliable sedation scale for use with mechanically ventilated patients in an adult surgical intensive care unit. Crit Care Med 1999; 27:1271-1275.

(17.) Corbett SM, Rebuck JA, Greene CM, Callas PW, Neale BW, Healey MA et al. Dexmedetomidine does not improve patient satisfaction when compared with propofol during mechanical ventilation. Crit Care Med 2005; 33:940-945.

(18.) Dasta JF, Jacobi J, Sesti A-M, McLaughlin TP. Addition of dexmedetomidine to standard sedation regimens after cardiac surgery: an outcomes analysis. Pharmacotherapy 2006; 26:798-805.

(19.) Herr DL, Sum-Ping STJ, England M. ICU sedation after coronary artery bypass graft surgery: dexmedetomidine-based versus propofol-based sedation regimens. J Cardiothorac Vasc Anesth 2003; 17:576-584.

(20.) MacLaren R, Forrest LK, Kiser TH. Adjunctive dexmedetomidine therapy in the intensive care unit: a retrospective assessment of impact on sedative and analgesic requirements, levels of sedation and analgesia, and ventilatory and hemodynamic parameters. Pharmacotherapy 2007; 27:351-359.

(21.) Martin E, Ramsay G, Mantz J, Sum-Ping ST. The role of the alpha2-adrenoceptor agonist dexmedetomidine in postsurgical sedation in the intensive care unit. J Intensive Care Med 2003; 18:29-41.

(22.) Siobal MS, Kallet RH, Kivett VA, Tang JF. Use of dexmedetomidine to facilitate extubation in surgical intensive-care-unit patients who failed previous weaning attempts following prolonged mechanical ventilation: a pilot study. Respir Care 2006; 51:492-496.

(23.) Takrouri MS, Seraj MA, Channa AB, el-Dawlatly AA, Thallage A, Riad W et al. Dexmedetomidine in intensive care unit: a study of hemodynamic changes. Middle East J Anesthesiol 2002; 16:587-595.

(24.) Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia 1999; 54:1136-1142.

(25.) Terajima K, Takeda S, Taniai N, Tanaka K, Oda Y, Asada A et al. Repeated dexmedetomidine infusions, a postoperative living-donor liver transplantation patient. J Anesth 2006; 20:234-236.

(26.) Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009; 301:489-499.

(27.) Venn M, Newman J, Grounds M. A phase II study to evaluate the efficacy of dexmedetomidine for sedation in the medical intensive care unit. Intensive Care Med 2003; 29:201-207.

(28.) Kobayashi A, Okuda T, Kotani T, Oda Y. [Efficacy of dexmedetomidine for controlling delirium in intensive care unit patients]. Masui 2007; 56:1155-1160.

(29.) Multz AS. Prolonged dexmedetomidine infusion as an adjunct in treating sedation-induced withdrawal. Anesth Analg 2003; 96:1054-1055.

(30.) Shehabi Y, Ruettimann U, Adamson H, Innes R, Ickeringill M. Dexmedetomidine infusion for more than 24 hours in critically ill patients: sedative and cardiovascular effects. Intensive Care Med 2004; 30:2188-2196.

(31.) Precedex Prescribing Information. eMIMS Australia; 2003.

(32.) Klimscha W, Tong C, Eisenach JC. Intrathecal alpha 2-adrenergic agonists stimulate acetylcholine and norepinephrine release from the spinal cord dorsal horn in sheep. An in vivo microdialysis study. Anesthesiology 1997; 87:110-116.

(33.) Mussi C, Ferrari R, Ascari S, Salvioli G. Importance of serum anticholinergic activity in the assessment of elderly patients with delirium. J Geriatr Psychiatry Neurol 1999; 12:82-86.

Address for correspondence: Dr Y. Shehabi: y.shehabi@unsw.edu.au

Y. SHEHABI *, H. NAKAE ([dagger]), N. HAMMOND ([double dagger]), F. BASS ([section]), L. NICHOLSON **, J. CHEN ([dagger dagger])

Acute Care Program, Intensive Care Department, Prince of Wales Hospital, Sydney, New South Wales, Australia

* M.B., B.S., F.J.F.I.C.M., F.A.N.Z.C.A., E.M.B.A., Medical Director, Acute Care Program, Director, Intensive Care Services and Research and Associate Professor, University of New South Wales Clinical School, Prince of Wales Hospital.

([dagger]) M.D., Consultant in Anaesthesia and Intensive Care, Department of Integrated Medicine, Division of Emergency and Critical Care Medicine, Akita University School of Medicine, Akita, Japan.

([double dagger]) M.N., ICU Clinical Research Nurse, The Prince Charles Hospital, Brisbane, Queensland.

([section]) B.N., Research Co-ordinator, Intensive Care Unit.

** B.N., Acting Nurse Educator, Intensive Care Unit.

([dagger dagger]) Ph.D., Senior Research Fellow, Simpson Centre for Health Services Research, The University of New South Wales.
Table 1
Individual patient characteristics *

Case   Age   Gender   Admission   Admission diagnosis
 no    (y)   (M/F)     APACHE
                      II score

 1      76     M         21       Postoperative
                                  respiratory
                                  failure and
                                  aspiration
                                  pneumonia

 2      71     M         17       CABG

 3      20     M         27       Rhabdomyolysis,
                                  acute renal failure

 4      74     M         15       Thoracotomy

 5      78     M         29       Decreased level of
                                  consciousness and
                                  fever

 6      70     F         16       Post CABG

 7      82     M         24       Self-inflicted stab
                                  wound to abdomen;
                                  small bow
                                  perforation

 8      48     M         23       Aspiration pneumonia,
                                  necrotising fasciitis

 9      52     M         18       Mitral valve
                                  regurgitation
                                  rapid AF

10      73     M         12       Continuous BIPAP,
                                  pneumonitis

11      76     M         28       Recent jejunal
                                  perforation worsening
                                  respiratory failure,
                                  ARDS

12      76     M         28       Recent jejunal
                                  perforation worsening
                                  respiratory failure,
                                  ARDS

13      61     M         16       Aortic and mitral
                                  valve replacement

14      51     M         18       Atypical pneumonia,
                                  sepsis liver abscess

15      79     M         14       Severe mitral valve
                                  regurgitation

16      74     M         14       Repair thoracic
                                  aortic aneurysm

17      49     M          9       CABG, respiratory
                                  failure

18      53     M         31       Post-renal
                                  transplant

19      26     M          6       Multiple trauma
                                  (chest fractures,
                                  closed head injury,
                                  spinal injury)

20      69     M         35       Sepsis, acute
                                  pancreatitis acute
                                  renal failure

21      74     M         47       Acute pancreatitis
                                  secondary to
                                  gallstone in common
                                  bile duct

22      51     M         30       Subdural haematoma,
                                  fractured left neck
                                  of femur

23      75     M         15       Oesophageal rupture

24      75     M         15       Oesophageal rupture

25      87     M         16       Leaking abdominal
                                  aortic aneurysm
                                  repair

26      35     M         22       Acute hepatitis
                                  continuous CVVHD

27      62     M         25       Exacerbation of
                                  COPD

28      33     M         26       Multiple trauma
                                  excluding head

29      62     M         16       CABG

30      82     M         17       CABG

Case   Co-morbidities           Infusions during          Duration
 no                            48 hours preceding       ventilation,
                                  Dex[dagger]            total (h)

 1     Asthma, HT, COPD,       Morphine 2 mg/h              126
       thrombocytopenia,       Midazolam 1 mg/h
       anaemia

 2     Type 2 diabetes, HT     Midazolam 3 mg/h              52
       IHD                     Propofol 135 mg/h

 3     Developmental delay,    Propofol 95 mg/h             189
       recent seizures,
       encephalopathy

 4     Paraplegia T3-T4,       Midazolam 2 mg/h             336
       HT, moderate            Ketamine 10 mg/h
       respirator failure

 5     HT, chronic renal       Propofol 60 mg/h             232
       failure (non-           Fentanyl 20 [micro]g/h
       dialysis dependent

 6     HT, recent myocardial   Fentanyl 10 [micro]g/h       106
       infarction, type 1      Midazolam 1 mg/h
       diabetes

 7     Type 1 diabetes, GIT    Fentanyl 40 [micro]g/h       319
       neoplasm, psychiatric   Midazolam 5 mg/h
       illiness

 8     Type 1 diabetes,        Fentanyl 50 [micro]g/h       191
       mobid obesity,          Midazolam 5 mg/h
       psychiatric illiness

 9     Hepatitis C             Morphine 1 mg/h               27
                               Propofol 300 mg/h

10     Pacemaker, pneumonia    Haloperidol 20 mg/h          235

11     HT, pulmonary           Propofol 100 mg/h            599
       fibrosis                Midazolam 2 mg/h
                               Fentanyl 20 [micro]g/h

12     HT, pulmonary           Midazolam 1 mg/h             599
       fibrosis                Fentanyl 10 [micro]g/h

13     Arrhythmias: AF         Propofol 150 mg/h             24
                               Fentanyl 30 [micro]g/h

14     COPD, prostatic         Propofol 60 mg/h             167
       hypertrophy             Fentanyl 10 [micro]g/h

15     Previously well         Morphine 2 mg/h              138
                               Midazolam 2 mg/h

16     TIA, HT, left-          Propofol 55 mg/h             456
       sided weakness          Midazolam 2 mg/h

17     AMI, HT                 Propofol 150 m/h             169
                               Fentanyl 50 [micro]g/h

18     End-stage renal         Propofol 40 mg/h              29
       failure AF, angina,
       gout

19     Transferred from        Missing data                  60
       another hospital

20     COPD, type 2            Propofol 30 mg/h             158
       diabetes AMI,           Fentanyl 20 [micro]g/h
       CCF

21     Chronic renal           Propofol 60 mg/h             133
       failure COPD, AMI,      Midazolam 3 mg/h
       left ventricle          Fentanyl 35 [micro]g/h
       dysfunction, AF,        PVD
       CVA type 2 diabetes,
       HT, PVD

22     Alcohol and             Propofol 70 mg/h             220
       recreational drug       Morphine 3 mg/h
       use                     Midazolam 2.5 mg/h

23     IHD, AF, HT, high       Morphine 3 mg/h              360
       cholesterol, gout       Midazolam 3 mg/h

24     IHD, AF, HT, high       Morphine 1.5 m/h             360
       cholesterol, gout       Midazolam 3 mg/h

25     HT, chronic renal       Fentanyl 15 [micro]g/h        37
       failure

26     Systemic lupus          None                         316
       erythematosus

27     GORD; severe COPD       Midazolam 2 mg/h             123
       on home oxygen                                    [section]

28     Previously well         Propofol 140 m/h             142
                               Morphine 3 mg/h
                               Midazolam 1 mg/h

29     IHD, previous          Propofol 125 mg/h            216
       CABG, COPD

30     HT, angina, CVA,       Propofol 75 mg/h             252
       AAA                    Midazolam 7.5 mg/h

Case     ICU        Maximum        Hours   Reason for cessation
 no      LOS        Dex dose      on Dex
       (days)   ([micro]g/kg/h)    1234

 1       7             0.6           36    Lack of efficacy, change
                                           to propofol

 2       4             0.7           66    Patient ready for ward

 3      10             1.0          120    Clinical deterioration,
                                           seizures requiring midazolam

 4      15             1.0           78    Sedation no longer required

 5      13             0.7           57    Prior to extubation at
                                           clinician discretion,
                                           clinically effective

 6       9             0.4           70    Sedation no longer required

 7      16             0.7           48    Clinician discretion

 8      16             1.0           48    Patient ready for ward
                                           Haloperidol 35 mg

 9     1.7             0.7           27    Patient ready for ward

10      19             1.0           60    Clinical deterioration,
                                           respiratory failure
                                           requiring intubation

11      25             1.0           83    Clinical deterioration,
                                           sepsis and haemodynamic
                                           severe instability

12      25             0.7           48    Clinical deterioration,
                                           required tracheostomy

13      25             1.0          144    Worsening of liver function

14       5             0.7           48    Lack of efficacy

15       7             0.7           27    Extubated; all sedation
                                           ceased

16      24             0.7           63    Clinician decision

17       3             0.7           51    Ready for extubation

18       5             0.7           61    Patient ready for ward

19       6             0.7           30    Patient ready for ward

20       8             0.6           48    Patient ready for ward

21       5             0.7         67.5    Lack of efficacy,
                                           continued agitation

22      11             0.7           72    Clinical deterioration
                                           requiring muscle relaxants
                                           and heavy sedation

23      26             0.6           43    Lack of efficacy, increasing
                                           doses of propofol and
                                           midazolam

24      26             0.7           24    Patient ready for ward

25       7             0.6           90    Haemodynamic instability
                                           requiring intubation,
                                           palliative therapy

26      24             0.6           72    No longer needed

27      15             1.0           78    Severe respiratory failure,
                                           isofluorane for ventilation

28      27             1.0          142    No longer needed

29     29             1.0           216    Patient ready for ward

30     31             0.7           252    No longer needed

* Note: there were 30 episodes in 28 patients; episodes 11 and 12
are in one individual, as are episodes 23 and 24. [dagger] Bolus
medications are not recorded, except for haloperidol. M=male,
F=female, APACHE II=Acute Physiologic and Chronic Health Evaluation
Score II, Dex=Dexmedetomidine, ICU=intensive care unit, LOS=length
of stay, HT=hypertension, COPD=chronic obstructive pulmonary disease,
CABG=coronary artery bypass graft, IHD=ischaemic heart disease,
GIT=gastrointestinal tract, BIPAP=bi-level positive airway pressure,
ARDS=acute respiratory disease syndrome, AF=atrial fibrillation,
TIA=transient ischaemic attacks, AMI=acute myocardial infarction,
CCF=congestive cardiac failure, CVA=cerebro-vascular accident,
PVD=peripheral vascular disease, CVVHD=continuous venovenous
haemodiafiltration, GORD=gastro-oesophageal reflux disease,
AAA=abdominal aortic aneurysm.

Table 2
Cohort clinical characteristics (n=30)

Variable                   Dexmedetomidine
                               (n=30)

Age, median years [IQR]     70.5 [51-76]

Males, %                    96.7

APACHE II score,            18 [15-27]
median [IQR]

Total ICU LoS,              14 [7-25]
median days [IQR]

Hospital LoS,               24 [16-31]
median days [IQR]

Episodes survived to ICU    24 (80.0)
discharge number (%)

Episodes survived to        24 (80.0)
hospital dicharge
number (%)

Dobutamine at                9 (30)
baseline, number (%)

Noradrenaline or            10 (33)
adrenaline at baseline
number (%)

Requiring reduced            7 (23.3)
vasopressors/inotropes,
number (%)

Requiring increased          1 (3.3)
vasopressors/inotropes,
number (%)

IQR=interquartile range, APACHE II=Acute Physiology and
Chronic Health Evaluation Score II, ICU=intensive care unit,
LoS=length of stay.

Table 3
Dexmedetomidine infusion and ventilation-related outcomes

Clinical outcome and infusion characteristics

Maximum dexmedetomidine dose,          0.70 [0.7-1.0]
[micro]g/kg/h, median [IQR]

Dexmedetomidine infusion time,         62 (24-252)
median hours (range)

Reason for ceasing dexmedetomidine     Number (%)

  Ceased as planned                    15 (50)

  Unrelated clinical deterioration     6 (20)

  Lack of efficacy at the dose use     4 (13.3)
  (maximum dose not used)

  Intensivist discretion               3 (10)

  Possible adverse events              2 (6.7)

Additional sedative/analgesics         Number (%)
up to 72h post-infusion

  Nil needed                           11 (37)

  Low dose propofol                    6 (20)
  infusion 5-30 mg/h

  Intermittent propofol boluses        2 (7)

  Low-dose fentanyl infusion           1 (3)
  10 [micro]g/h

  Haloperidol boluses (total 10 mg)    2 (6)

  Therapeutic fentanyl/midazolam/      5 (17)
  morphine propofol

  other agents (isoflurane,            2 (7)
  clonazepam)

Time ventilated prior to enrolment,    115 [87-263]
median hours [IQR]

Total ventilation time, median         179 [123-315]
hours [IRQ]

Post-infusion ventilation time,        70 [28-96]
median hours [IQR]

Extubated on dexmedetomidine           10 (33)
infusion, number (%)

Post-infusion tracheostomy,            3 (10.0)
number (%)

IQR=interquartile range.

Figure 1: Sedation score categories at 0, 6 and 12 hours after
commencing dexmedetomidine infusion. This histogram shows Motor
Activity Assessment Scores (MAAS) at 0, 6 and 12 hours from
dexmedetomidine infusion. At 0 hours, 23 (77%) patients were either
agitated or over-sedated--within 6 hours of the infusion 28 (93%)
patients were within target MAAS range of 2 to 4. Two-sided Fisher's
exact test P <0.0001. This was maintained at 12 hours and at 24
hours (data not shown).

                  Number of
                  patients
                  episodes
                  (n = 30)

MAAS category   0h   6h   12h

Very agitated   5    0    1
Agitated        10   2    3
Target          7    28   26
Over-sedated    8    0    0

Note: Table made from bar graph.
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Article Details
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Author:Shehabi, Y.; Nakae, H.; Hammond, N.; Bass, F.; Nicholson, L.; Chen, J.
Publication:Anaesthesia and Intensive Care
Article Type:Clinical report
Geographic Code:9JAPA
Date:Jan 1, 2010
Words:5441
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