Brief Review: Delirium

Evan D. Schmitz, MD

Jack B. Vu, MD

University of Washington

Seattle, WA

A significant number of patients develop a decline in cognitive function while hospitalized. Delirium in the intensive care increases mortality and healthcare costs and should be recognized and treated promptly (1,2). 

This is a brief review of delirium and important treatment options such as early percutaneous tracheostomy, neuroleptics, propofol, daily awakenings and reorientation by all team members. We recommend neither neuroimaging nor neurology consultation unless physical exam suggests an acute cerebral vascular accident or status epilepticus as the majority of these patients require no neurologic intervention and may be harmed by transportation to obtain additional testing.

The DSM-5 defines delirium as a disturbance in attention (reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment). The disturbance develops over a short period of time (usually hours to a few days), represents a change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day. Delirium may also be a disturbance in cognition (memory deficit, disorientation, language, visual spatial ability, or perception).

The leading cause of delirium in the intensive care unit is metabolic encephalopathy caused by the patient’s primary disease and exacerbated by treatment with life saving measures such as intubation with mechanical ventilation. The required anesthesia and analgesia during intubation contribute to worsening delirium. The quicker the patient is extubated, the better is the overall prognosis. Delirium makes it more difficult to extubate the patient, independent of the disease process as the clinician is uncertain if the patient will be able to protect their airway and breathe on their own. This is further compounded by the increasing need for nursing during this critical period. There are numerous studies showing the benefits of sedation vacation and reorientation by nursing. If you were to speak with nurses they will tell you how difficult it is dealing with a delirious patient as the patient can become combative and difficult to console. As hospitals continue to cut back on nurses, nursing aids, respiratory therapists and sitters, it becomes increasingly more difficult to care for these patients.

Nursing is one of the most dangerous careers according to the U.S. Bureau of Labor (3). Delirium is directly responsible for traumatic injuries nurses suffer from combative patients while caring for the critically ill. It is therefore understandable why a majority of nurses are concerned when they are told to extubate these delirious patients.

We make it a point to educate nurses that they should extubate the patient as soon as possible. Once a plan is established, including neuroleptics to control agitation, it is important that the physician conducts bed rounds on the patient multiple times during the day. The physician should also explain to the nocturnal staff the importance of avoiding re-intubation, as these delirious patients do respond to neuroleptics and redirection. We only recommend extubation if the whole team is on board.

We have been performing percutaneous tracheostomies since 2006 and have noticed a significant decrease in ventilator days and duration of delirium in those patients receiving this surgery. Once a percutaneous tracheostomy is placed, a patient can be ventilated with minimal or no sedatives which allows improvement in their cognitive function.

Immediately after paralytics have worn off after performing a bedside percutaneous tracheostomy, we stop all sedatives and narcotics to allow the patient to regain consciousness. We use neuroleptics to treat delirium while awaiting for the return of cognitive function. With a tracheostomy in place, the respiratory therapists and nurses appear much more comfortable allowing patients to recover without giving any narcotics or sedatives resulting in a much faster recovery. Patients with neurological impairment, including delirium, demonstrate tachypnea out of proportion to their respiratory needs. Recognition of this type of breathing pattern is important. Educating the staff about this type of breathing pattern also helps nurses and respiratory therapists to cope with the resultant high minute ventilation. If there are periods of apnea with irregular periods of hyperventilation, the breathing pattern is called Biot’s breathing (4).

Once placed, percutaneous tracheostomy as opposed to endotracheal intubation, requires neither anesthetic nor analgesic. Since the tracheostomy is usually placed between the first and second tracheal cartilaginous rings, the vocal cords are free from damage including swelling that occurs with endotracheal tubes. Endotracheal tubes are very uncomfortable and analgesia and anesthesia are required to keep patients comfortable. This can cause delirium. The incidence of tracheal stenosis does not appear to be greater with percutaneous tracheostomy as opposed to endotracheal intubation.

Percutaneous tracheostomy can be performed safely at the bedside in the intensive care unit. As long as one physician is controlling the airway while performing direct visualization via bronchoscopy and the other is performing the percutaneous tracheostomy, any adverse complications can be managed promptly. Remember to place a sign in the patient’s room warning staff not to replace the tracheostomy if it were to fall out within the first seven days and to call a code for prompt intubation. This will avoid misplacement which can lead to death.

Although we are not recommending tracheostomy just for the treatment of delirium, we do recommend early tracheostomy within a few days as opposed to waiting to perform a tracheostomy when anticipated ventilation is longer than ten days. Most of our colleagues who perform percutaneous tracheostomy agree (Schmitz ED, unpublished observations.

Haloperidol (Haldol®) has been around for decades. Haloperidol is a butyrophenone antipsychotic which acts primarily by blocking postsynaptic mesolimbic dopaminergic D2 receptors in the brain. This results in depression of the reticular activating system (5).

As opposed to sedatives and analgesics, haloperidol does not suppress intellectual function or cause respiratory failure. It appears underutilized because of concern about prolonging the QT interval and increasing the risk for a cardiac arrhythmia (6). Although it is true that neuroleptics can prolong the QT interval, the fear associated with this rare phenomenon inhibits the use of the most effective treatment for delirium we have at our disposal. 

Newer antipsychotics such and olanzapine, risperidone and ziprasidone may be used as well, but they also have been associated with inducing cardiac arrhythmias. These drugs appear to have less extrapyramidal side effects caused by the excitatory actions of unopposed cholinergic neurons. These newer antipsychotics block the serotonin receptor 5HT and to a lesser extent D2, and therefore, they decrease the likelihood of acute dystonic reactions, pseudo-parkinsonism, akathisia and tardive dyskinesia (7).

We have had great success with intravenous haloperidol. We recommend starting with a 5-10 mg intravenously and repeating this dose every 15 minutes until the patient’s agitation is controlled. We then schedule haloperidol intravenously as needed. Depending on which newer neuroleptics are available, we schedule these drugs until the patient recovers from their delirium. We have also had success with sublingual or intramuscular olanzapine 10 mg every 8 to 12 hours. Much higher doses, greater than 200 mg a day, have been reported in hospice patients without adverse cardiac effects (8).

Prior to instituting neuroleptics, ensure that the patient’s electrolytes are normal which will decrease the likelihood of an arrhythmia. Try to avoid haloperidol in patients with Parkinson’s disease because it diminishes the availability of dopamine.

An additional measure to decrease the risk and length of delirium is by using propofol and fentanyl for sedation rather than a benzodiazepine. Recent studies have shown that using propofol instead of a benzodiazepine decreases mortality, ventilator days and delirium (9). The elderly and those with liver impairment appear to benefit the most from propofol because of the faster metabolism of this class of drug. Side effects such as hypotension can be easily managed with fluids and a low dose of norepinephrine.

Renal failure is common in critically ill patients. It is important to monitor patients closely for signs of uremic encephalopathy which occurs when patients are unable to adequately excrete nitrogenous waste and other factors (10).

Nitrogen is excreted by the kidneys as urea and ammonium. Amino acids are catabolized by transamination which is the process of transferring their alpha-amino group to alpha-ketoglutarate which produces glutamate. The two most important are alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Alpha-ketoglutarate is an essential intermediate substrate in the citric acid cycle (11).

Glutamate can be oxidized to form free ammonia or it can combine with ammonium in the presence of ATP to form glutamine in the muscle, liver and nervous system providing a nontoxic storage and transport form of ammonia. 

In renal failure hyperammonemia occurs leading to tremors, slurring of speech and blurring of vision. In the presence of elevated ammonia, alpha-ketoglutarate combines with ammonia to form glutamate. Glutamate accumulates which causes cytotoxicity to nerve cells and death via NMDA-type synapses which mediate calcium influx (5). As the concentration of alpha-ketoglutarate declines, the brain cannot produce the energy it needs through the citric acid cycle which can lead to coma and death.

Although drugs used to treat hyperammonemia in patients with liver failure such as neomycin, lactulose and rifaximin will help decrease the amount of urea and ammonia reabsorbed in the intestines, in patients with renal failure, dialysis is imperative to recovery. After only one treatment with dialysis, the cognitive improvement is profound. As the acute kidney injury resolves, dialysis is no longer necessary.

It is unclear whether antiepileptics can also help with delirium. Valproic acid may inhibit glutamates action on the NMDA receptor. Glutamate mediated neuronal excitotoxicity has been postulated as a cause of nerve cell death. Antiepileptics may be beneficial at attenuating the deleterious effects of glutamate in the brain.

Delirium can also be caused by too much serotonin. Medications such as serotonin re-uptake inhibitors (SSRIs), linezolid, metoclopramide, fentanyl and baclofen can cause the serotonin syndrome. Patients typically exhibit some type of clonus (12). We recommend stopping all antidepressants in critically ill patients exhibiting signs of delirium. After the delirium subsides, resuming the SSRI appears appropriate. Depression is common as patients recover from their critical illness and the addition of an SSRI may be beneficial prior to transfer out of the intensive care unit.

By adhering to the above recommendations, you will be able to recognize delirium and institute effective lifesaving treatments. Patients and their family members will be grateful as they will be able to communicate with their loved ones once again. Nurses will also be happier as they will suffer less emotional and physical trauma. This will lead to a faster patient recovery and a shorter length of hospitalization.

References

1. Yamaguchi T, Tsukioka E, Kishi Y. Outcomes after delirium in a Japanese intensive care unit. Gen Hosp Psychiatry. 2014;36(6):634-6. [CrossRef] [PubMed]
2. Hsieh SJ, Soto GJ, Hope AA, Ponea A, Gong MN. The Association Between ARDS, Delirium, and In-hospital Mortality in ICU Patients. Am J Respir Crit Care Med. 2014 Nov 13. [Epub ahead of print] [CrossRef] [PubMed]
3. U.S. Department of Labor, Bureau of Labor Statistics. Lost-worktime injuries and illnesses: characteristics and resulting time away from work 2010. Available at: http://www.bls.gov/news.release/osh2.nr0.htm (accessed 12/22/14).
4. Wijdicks EF. Biot's breathing. J Neurol Neurosurg Psychiatry. 2007;78(5):512-3. [CrossRef] [PubMed]
5. Waxman SG. Clinical Neuroanatomy. 25th edition. New York, NY: McGraw Hill Medical; 2003.
6. Hatta K, Kishi Y, Wada K, Odawara T, Takeuchi T, Shiganami T, Tsuchida K, Oshima Y, Uchimura N, Akaho R, Watanabe A, Taira T, Nishimura K, Hashimoto N, Usui C, Nakamura H. Antipsychotics for delirium in the general hospital setting in consecutive 2453 inpatients: a prospective observational study. Int J Geriatr Psychiatry. 2014;29(3):253-62. [CrossRef] [PubMed]
7. Howland RD. Phamacology. 3rd edition. Philadelphia. Lippincott, Williams & Wilkins. 2003. Howland RG. Pharmacology. 3rd edition. Philadelphia, PA: Lippincott, Williams and Wilkins; 2006.
8. Bascom PB, Bordley JL, Lawton AJ. High-dose neuroleptics and neuroleptic rotation for agitated delirium near the end of life. Am J Hosp Palliat Care. 2014;31(8):808-11. [CrossRef] [PubMed]
9. Lonardo NW, Mone MC, Nirula R, Kimball EJ, Ludwig K, Zhou X, Sauer BC, Nechodom K, Teng C, Barton RG. Propofol is associated with favorable outcomes compared with benzodiazepines in ventilated intensive care unit patients. Am J Respir Crit Care Med. 2014;189(11):1383-94. [CrossRef] [PubMed]
10. Scaini G, Ferreira GK, Streck EL. Mechanisms underlying uremic encephalopathy. (10) Rev Bras Ter Intensiva. 2010;22(2):206-211. [CrossRef] [PubMed]
11. Champe PC, Harvey RA. Biochemistry. 2nd edition. Philadelphia:JB Lippincott-Raven;1994.
12. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-20. [CrossRef] [PubMed] 

Reference as: Schmitz ED, Vu JB. Brief review: delirium. Southwest J Pulm Crit Care. 2014;9(6):343-7. doi: http://dx.doi.org/10.13175/swjpcc166-14 PDF

Analysis of Overall Level of Evidence Behind The Institute of Healthcare Improvement Ventilator-Associated Pneumonia Guidelines

Reference as: Padrnos L, Bui T, Pattee JJ, Whitmore EJ, Iqbal M, Lee S, Singarajah CU, Robbins RA. Analysis of overall level of evidence behind the Institute of Healthcare Improvement ventilator-associated pneumonia guidelines. Southwest J Pulm Crit Care 2011;3:40-8. (Click here for PDF version of manuscript)

Leslie Padrnos^1,4(lpadrnos@email.arizona.edu)

Tony Bui^1,4 (tony.bui@cox.net)

Justin J. Pattee^2,4 (backageyard@gmail.com)

Elsa J. Whitmore^2,4 (elsa_whitmore@hotmail.com)

 Maaz Iqbal^1,4 (maaziqbal@gmail.com)

Steven Lee^3,4 (timmah2k@gmail.com)

Clement U. Singarajah^2,4 (clement.singarajah@va.gov)

 Richard A. Robbins^1,4,5 (rickrobbins@cox.net)

¹University of Arizona College of Medicine

²Midwestern University-Arizona College of Osteopathic Medicine

³Kirksville College of Osteopathic Medicine

⁴Phoenix VA Medical Center

⁵Phoenix Pulmonary and Critical Care Research and Education Foundation

None of the authors report any significant conflicts of interest.

Abstract

Background 

Clinical practice guidelines are developed to assist in patient care but the evidence basis for many guidelines has recently been called into question.

Methods 

We conducted a literature review using PubMed and analyzed the overall quality of evidence and made strength of recommendation behind 6 Institute of Health Care (IHI) guidelines for prevention of ventilator associated pneumonia (VAP). Quality of evidence was assessed by the American Thoracic Society levels of evidence (levels I through III) with addition of level IV when evidence existed that the guideline increased VAP. We also examined our own intensive care units (ICUs) for evidence of a correlation between guideline compliance and the development of VAP.

Results 

None of the guidelines could be given more than a moderate recommendation. Only one of the guidelines (head of bed elevation) was graded at level II and could be given a moderate recommendation. One was graded at level IV (stress ulcer disease prophylaxis). The remainder were graded level III and given weak recommendations. In our ICUs compliance with the guidelines did not correlate with a reduction in VAP (p<0.05).

Conclusions 

Most of the IHI guidelines are based on level III evidence. Data from our ICUs did not support guideline compliance as a method of reducing VAP. Until more data from well-designed controlled clinical trials become available, physicians should remain cautious when using current IHI VAP guidelines to direct patient care decisions or as an assessment of the quality of care.

Introduction

The growth of guideline publications addressing nearly every aspect of patient care has been remarkable. Over the past 30 years numerous medical regulatory organizations have been founded to improve the quality of care. Many of these organizations have developed medical regulatory guidelines with 6870 listed in the National Guideline Clearinghouse (1). Many of these guidelines were rapidly adopted by healthcare organizations as a method to improve care.

Interest has grown in critically appraising not only individual clinical practice guidelines but also entire guideline sets of different medical (sub)specialties based on their rapid proliferation and in many instances an overall lack of efficacy in improving care (2,3). We assessed the quality of evidence underlying recommendations from one medical regulatory organization, the Institute for Healthcare Improvement (IHI), regarding one set of guidelines, the ventilator associated pneumonia (VAP) guidelines or VAP bundles (4). This was done by senior medical students during a month long rotation in the Phoenix Veterans Administration ICU. 

Methods

The study was approved by the Western Institutional Review Board.

Literature Search

In each instance PubMed was searched using VAP which was cross referenced with each component of the VAP bundle (as modified by the Veterans Administration) using the following MESH terms: 1. Elevation of the head of the bed; 2. Daily sedation vacation; 3. Daily readiness to wean or extubate; 4. Daily spontaneous breathing trial; 5. Peptic ulcer disease prophylaxis; and 6. Deep venous thrombosis prophylaxis. In addition, each individual component of the term was cross referenced with VAP. We also reviewed “Related citations” as listed on PubMed. Additional studies were identified using the “Related citations” in Pubmed from studies listed as supporting evidence on the IHI website and from the references of these studies.

Each study was assessed for appropriateness to the guideline. Studies were required to be prospective and controlled in design. Only studies demonstrating a reduction in VAP were considered, i.e., surrogate outcomes such as reduction in duration of mechanical ventilation were not considered. 

The American Thoracic Society grading system was used to assess the underlying quality of evidence for the IHI VAP guidelines (5) (Table 1). Only evidence supporting a reduction in VAP was considered. We added category IV when there was literature evidence of potentially increasing VAP with the use of the recommendation. A consensus was reached in each case. 

Table I. Levels of Evidence

Level of Evidence	Definition
Level I (high)	Evidence from well-conducted, randomized controlled trials.
Level II (moderate)	Evidence from well-designed, controlled trials without randomization (including cohort, patient series, and case-control Studies). Level II studies also include any large case series in which systematic analysis of disease patterns was conducted, as well as reports of data on new therapies that were not collected in a randomized fashion.
Level III (low)	Evidence from case studies and expert opinion. In some instances, therapy recommendations come from antibiotic susceptibility data without clinical observations.
Level IV	No evidence of improvement with some evidence of an increase in a negative outcome.

Guideline Compliance and VAP Incidence

We also assessed our ICUs for additional evidence of the effectiveness of the VAP bundle. Data was collected for a period of 50 months from January, 2007 through February, 2011. This was after the Veterans Administration requirements for VAP reporting and IHI compliance was instituted. Diagnosis and compliance were assessed by a single quality assurance nurse using a standardized protocol (6). Statistical analysis was done using a Pearson correlation coefficient with a two-tailed test. Significance was defined as p<0.05.

Results

Literature Review

Numbers of articles identified by PubMed search and used for grading the level of evidence and strength of recommendation are given in Table 2. Also included are the level of evidence and the strength of the recommendation.

Table 2.

Guideline

Total Articles

No. of Articles Used (references)

Level of Evidence

Strength of Recommendation

Elevation of the head of the bed	31	8 (7-14)	II	Moderate
Daily sedation vacation	66	4 (15-18)	III	Weak
Daily readiness to wean or extubate	47	3 (19-21)	III	Weak
Daily spontaneous breathing trial	29	1 (22)	III	Weak
Peptic ulcer disease prophylaxis	52	9 (23-29)	IV	Weak
Deep venous thrombosis prophylaxis.	14	2 (30-31)	III	Weak

Head of Bed Elevation

A literature search identified 31 articles of which 8 were used in evaluating this guideline (7-14). However, only 2 specifically studied head of bed elevation with one supporting and another not supporting the intervention (7,8). Consequently it was graded as level II and the strength of recommendation was graded as moderate.

Daily Spontaneous Breathing Trial, Daily Readiness to Wean, and Daily Sedation Vacation

From 1-4 studies were identified for each of these interventions, however, none demonstrated a reduction in VAP. Consequently, it was judged that the evidence basis was level III and the strength of recommendation was graded as weak.

Stress Ulcer Disease Prophylaxis

We found no evidence that stress ulcer disease prophylaxis decreased VAP (23-29). There was some evidence that acid suppressive therapy increased pneumonia and VAP. Consequently, it was judged to be a level IV (possibly increasing VAP). 

Deep Venous Thrombosis Prophylaxis

We could find no evidence that deep venous thrombosis prophylaxis decreased VAP (30,31).

Guideline Compliance and VAP Incidence

Beginning in the first quarter of fiscal year 2007 there was a significant decrease in the incidence of VAP in our hospital (33). This coincided with the requirement for the monitoring of VAP, compliance with the VAP bundles and our adoption of endotracheal aspiration with nonquantitative culture of the aspirate as opposed to bronchoalveolar lavage which had been out standard practice. We changed practices because bronchoalveolar lavage with quantitative cultures appeared to offer no improvement in clinical outcomes to endotracheal aspiration (34). In our medical and surgical ICUs, 5097 audits representing 5800 ventilator-days were assessed. Nineteen cases of VAP were identified with an average of 2.1 VAP infections/1000 ventilator-days.  We assessed our surgical and medical ICUs, combined and separately, for a correlation between total bundle compliance and each component of the VAP bundle with VAP incidence (Appendices 1-3). There was no significant correlation between compliance with the bundles and VAP (p<0.05).

Discussion

This manuscript questions the validity of the VAP bundles as proposed by the IHI. We found that a systematic review of the literature revealed predominately weak evidence to support these guidelines. Only one guideline (head of bed elevation) was supported by a randomized trial (7), but an additional, larger trial showed no decrease in VAP (8). Furthermore, data from our own ICUs showed no evidence of IHI VAP guideline compliance with a reduction in VAP.

Head of bed elevation is a relatively simple and easy to perform intervention which may reduce VAP. Studies examining aspiration have shown a reduction in critical care patients with the head of bed elevation but it is unclear whether this translates into a reduction in VAP (36,37). Drakulovic et al. (7) reported a randomized controlled trial in 86 mechanically ventilated patients assigned to semi-recumbent or supine body position.  The trial demonstrated that suspected cases of ventilator-associated pneumonia had an incidence of 34 percent while in the semi-recumbent position suspected cases had an incidence of 8 percent (p=0.003).  However, another study in 221 subjects demonstrated that the target head elevation of 45 degrees was not achieved for 85% of the study time, and these patients more frequently changed position than supine-positioned patients (8). The achieved difference in treatment position (28 degrees vs. 10 degrees) did not prevent the development of ventilator-associated pneumonia. The other 5 articles identified either did not identify head of bed elevation directly or as part of a bundle. Most were a before and after design and not randomized. Therefore, it is difficult to draw any meaningful conclusions.

The IHI groups daily "sedation vacations" and assessing the patient’s “readiness to extubate.” The logic is that more rapid extubation leads to a reduction in VAP. Kress et al. (15) conducted a randomized controlled trial in 128 adult patients on mechanical ventilation, randomized to either daily interruption of sedation irrespective of clinical state or interruption at the clinician’s discretion. Daily interruption resulted in a reduction in the duration of mechanical ventilation from 7.3 days to 4.9 days (p=0.004). However, in a retrospective review of the data, the authors were unable to show a significant reduction in VAP (16).

Stress ulcer prophylaxis and deep venous thrombosis prophylaxis are routine in most ICUs. However, stress ulcer prophylaxis with enteral feeding is probably as effective as acid suppressive therapy and acid suppressive therapy may increase the incidence of VAP (38). Deep venous thrombosis prophylaxis has been shown to decrease the incidence of pulmonary emboli but not improve mortality (32). Although we use these interventions in our ICU, we would suggest that these would be more appropriate for recommendations rather than guidelines.

The diagnosis of VAP is difficult, requiring clinical judgment even in the presence of objective clinical criteria (6). The difficulty in diagnosis, along with the negative consequences for failure to follow the IHI guidelines, makes before and after comparisons of the incidence of VAP unreliable. Therefore, we sought evidence for the effectiveness of VAP prevention guidelines reasoning that the better the compliance with the guidelines, the lower the incidence of VAP. We were unable to show that improved VAP guideline compliance correlated with a reduced incidence of VAP.

The IHI guidelines would not meet the criteria outlined earlier in an editorial in the Southwest Journal of Pulmonary and Critical Care for a good guideline:

Our study has several limitations. No literature review is totally comprehensive. It is possible that studies relevant to the IHI VAP guidelines, especially those written in a foreign language, were not identified. Second, the Phoenix VA data may be underpowered to show a small beneficial effect despite having over 5000 patient audits. Third, as with other healthcare facilities, the VAP guidelines at our institution were mandated and monitored. The threat of negative consequences may have compromised the objective assessment of the data, likely invalidating a before and after comparison. Fourth, correlation between guideline compliance and VAP incidence is not a substitute for a randomized trial. Unfortunately, the later is not possible given that guideline compliance is mandated.

It is unclear why the IHI guidelines have received such wide acceptance given their weak evidence basis. Agencies involved in guideline writing should show restraint in guideline formulation based on opinion or weak or conflicting evidence. Only those interventions based on strong evidence which can make a real difference to patients should be designated as guidelines.

Acknowledgements

The authors acknowledge Janice Allen, MSN, RN who collected the VAP data reported from the Phoenix VA.

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Appendices

Click here for Appendix 1. VAP rate in all ICUs

Click here for Appendix 2. VAP in medical ICU

Click here for Appendix 3. VAP in surgical ICU