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Levels of Sedation - Dissertation Sample

15 Mar 2017Dissertation Samples

Levels of sedation and its effects on prolonging mechanical ventilation in critically ill adults

Ventilation and sedation is a procedure that is commonly seen in ITUs and other critical care establishments. It can be use for  a number of different therapeutic reasons and to help to treat a number of different clinical situations.(Marx WH et al 1999)

The need for mechanical ventilation is one of the main criteria for admission to and ITU. This is usually administered by endotracheal intubation (occasionally by tracheostomy) and sedation. Sedation is clearly needed for the intubation to be tolerated, but the degree of sedation is more often then not a matter of professional clinical judgement on the part of the responsible anaesthetist. It is a common observation that optimal sedation levels can both improve the quality of care and also reduce its duration in terms of time.(Rainey TG et al. 1998). It also therefore follows that this may well also reduce the time spent in intensive care. (Kollef et al 1998 (I)

Equally inappropriate or excessive amounts of sedation can increase the length of time spent on the ventilator which has it’s own disadvantages and harmful effects. (Kollef et al 1998) (II)

The purpose of this literature review is to examine the rationales and evidence base behind this combination of therapy. (Berwick D   2005)

Literature review

A good starting point for our considerations is the paper by Brattebø G (et al 2002). It takes as read, our original premise that optimal levels of sedation are imperative for optimal levels of outcome on ventilated patients. It accepts the need for devising some kind of protocol to allow for an improved sedation strategy. The authors devised an observational study which not only introduced guidelines for sedation control, but interestingly also took the opportunity to observe and analyse the actual methods of adoption as the medical and nursing staff tried to implement it. It is this second part of the study design that perhaps sets it apart from many of the prospective studies that we will be reviewing here. (Cochran and Cox. 1957)

The NHS has learned many lessons relating to change management. In an organisation as large and cumbersome as the NHS, the effective introduction of new (or even good) ideas needs careful implementation management. Over the years the NHS has witnessed (and suffered from) the inept management of a newly introduced concept. (Nickols F.2004)

The concept may be good, but the method of its introduction can render it useless. (Berwick D. 1996)

Clinicians who have been in practice for more than twenty five years will remember the debacle of the disastrous introduction of the Griffiths Report (Griffiths Report 1983).

Many would say that, in principal, it was a good workable system, but it’s introduction and implementation was so inept that it was withdrawn before it could reach a fraction of its full potential. (Davidmann 1988) Brattebø’s paper takes stock of this potential for poor implementation and both analyses and assesses the protocol’s introduction to be able to draw appropriate conclusions on the matter.

The study was not on a large scale but this allowed for more careful and intimate observation of the issues under investigation. It was set in one ITU in a University hospital and encompassed all staff and patients (over 18) passing through the unit over an 11 month period.

One interesting strategy was that the authors considered and evaluated different methods of achieving staff conformance as the study progressed, and progressively adopted those methods that were found to be the most effective. (Carey et al. 1995)

The paper is both long and involved. The important outcomes of the investigation were that by optimising the sedation given to the patients, the mean ventilator time decreased by 2.1 days (from an average 7.1 days before the trial to 5.3 days after it). This also allowed a reduction in the mean period of time spent in the ITU by an average of one day (9.3 days to 8.3 days). The authors also record that these reductions and efficiencies were not associated with any increase in adverse incidents (accidental extubations etc.). One particularly significant comment made by the authors was:-

Lessons learnt: Relatively simple changes in sedation practice had significant effects on length of ventilator support. The change process was well received by the staff and increased their interest in identifying other areas for improvement.

The authors describe their methodology as using the “breakthrough method” (Marx et al. 1999) in which they make use of multiple short cycle improvements (Plesk PE 1999). They describe the method as entailing:

Setting goals, choosing appropriate small changes, and measuring whether the changes do lead to improvements; if so, the changes are incorporated in the departmental routines (Rainey et al 1998).  

The backbone of the study was the concept that, in cases of respiratory failure of any cause, patients are generally given both sedation and analgesia most often by the method of continuous infusion. (Brook AD et al 1999)

Commonly, the responsible clinician tends to err on the side of safety and prescribe heavier doses than may actually be necessary, with the result that the patient becomes more heavily sedated than may be required. (Kreiss et al 2000), and the corollary of this is that the patient will tend to spend more time on a ventilator than is absolutely necessary (Kollef M et al. 1998 (I)).

The alternative, say the authors, is to introduce a scoring system which can quantify when the sedation is “sufficient but not excessive” so that the lowest rates of sedative infusion can be achieved with the use of occasional supplemental bolus doses (Barr et al 1995). The natural inference with this system is that this will reduce the time spent on the ventilator. As we have discussed, this was one of the outcome measures of the study.

The actual process is described in detail in the paper and therefore we will not present it here, but it hinged on the application of the MAAS scale (Devlin et al 1999) and correlation with the degree of sedation that was required to produce a particular score on that scale.

The protocol and introduction of the scheme appears to have been managed meticulously well with multiple staff presentations, wall posters, feedback questionnaires, and other management tools. (Shortell SM et al. 1998),

The key note to absorb from this study is that the application of this system resulted in a 30% reduction in ventilator time for the patient on this particular ITU. A fully critical appraisal would have to observe that this could simply be a predictable result  from the introduction of a fixed protocol in a system of lax and unmanaged clinical practice which allowed for a 30% overuseage in ventilator time in the unit. There is no evidence to support or refute this point of view, but it would be charitable to assume that the clinical staff were doing what they thought best at the time. This method allowed them to have a more precise control over the sedation levels achieved. (Henriksen and Kaplan  2003)

It is interesting to note that the authors stated that as the intervention was aimed primarily at the clinical staff, it was not considered necessary  to get patient consent. Although clearly it would have been difficult to obtain direct patient consent, we have to express surprise that proxy consent was not obtained on behalf of the patients from the relatives. (Sugarman J & Sulmasy 2001)

We can now turn our attentions to a paper that we have quoted in support of a point in the Brattebø paper. Kreiss (et al 2000) produced a paper that took a similar approach but with different methodology. This study arose from the observation that continuous sedation levels tended to impede the clinical assessment of the patient and that it was common practice to allow “windows” of lighter sedation to allow neurological assessments together with assessments of the mental state. (Kong et al 2003)

The study compared the outcomes of one group who received reduced sedation at the discretion of the responsible clinician, who determined when appropriate neurological examination was necessary, with the outcomes from a second group who were “woken” on a daily basis irrespective of clinical need. (Brock et al 1998) A critical assessment would have to conclude that the cohort was not particularly large (with about 60 patients in each group), although it is accepted that the numbers of patients available for such a study are, by necessity, limited.  (Grimes et al. 2002)

The results however,  showed surprisingly different outcomes in the two groups.  The mean time on ventilation and sedation in the control group was 7.3 days but was only 4.9 days in the intervention group. It also showed an even more marked reduction in average time in ITU than the Brattebø study, of 9.9 days (control group) to 6.4 days (intervention group).

It should be noted that in this study a number of adverse incidents occurred, including three patients in the intervention group who removed their endotracheal tube.  (Vassal et al 1998)

This actually compared favourably with four who removed their tubes in the control group  (see on)

In the aftermath of the Kreiss paper, Gorman (et al 2004) published a similar study, which considered the effect of interruption of the continuous levels of sedation when patients were undergoing mechanical ventilation in the ITU.

Their object was to assess whether this did have any effect on the length of time that the patient spent on the ventilator. The study was not particularly large (by study standards) but was large in comparison with other ITU based studies with an initial entry cohort of 150 patients.

In contract to the Kollef study (Kollef et al 1998 – see on), this study was truly randomised once the inclusion criteria had been met into two groups. One group had continuous infusion of sedation and the other group were woken daily and then restarted on a regime which entailed recommencing half the dose of medication and then retitrating until the required level of sedation was reached which was defined as level 3-4 on the Ramsay scale. (Brock WA et al. 1998)

In addition both groups were randomly subdivided further to be sedated with either midazolam or propofol, so there were actually four investigation groups.

In broad terms, the outcome measures were the length of time that the patients spent on the ventilator together with the overall time they spent in the ITU and how these outcomes correlated with the method of administration of the appropriate sedative.

Before we consider the results, we must consider the structure of the trial. And compare it with the seemingly similar Kollef trial. There are two major differences in this trial’s design which make it significantly different from Kollef’s trial. One very significant point in the design of the Koleff  trial was the fact that the control group was sedated to Ramsay 3-4 levels in order to match the required levels in the intervention group. 

Although this clearly makes for easier and more direct comparison, it is possible that this level of sedation may actually have been greater than was actually required for that particular patient. This may have had the effect of being a significant  confounding factor in the eventual findings with regard to ventilation time. 

The second problem was that the Koleff study was not truly “blinded” as although the treating physicians did not know which group their patients had been assigned to, the structure of the study required a recording nurse to sit with the patient to record their levels of sedation at all times. This could not fail to have been noticed by the clinicians in charge of the case, and may have introduced a source of bias into the results.

The Gorman trial took account of both of these features so that they were not potential confounding factors in the newer study. The results were still similar although now possibly more statistically valid. The interruption group required less time on the ventilator and less time in hospital than the continuous infusion group. The authors note that these recommendations of interrupted sedation and retitration, have now become standard recommendations for the guidance of clinicians in the ITU setting. (Jacobi et al.2002)

We have refered to the complication of unintentional extubation (UEX) of the patient. This is an unusual but occasional consequence of lightening the sedation level of a patient who is being mechanically ventilated. (Esteban et al 1999 (I)

It is enlightening to therefore consider the study by Boulain (1998) who reviewed this phenomenon. The author took the potentially rather unpromising step of designing a prospective cohort trial to examine the occurrence. He followed nearly 450 patients over a two month period. in the study he recorded that over 10% of patients had at least one episode of unexpected extubation  during the study period, which is rather higher than some of the other authorities have reported.  (Krinsley JS & Barone JE 2005) (Epstien et al 2000). The direct relevance to our considerations comes from the sentence:

 
By use of multivariate analysis, we identified four factors contributing to unexpected extubation : chronic respiratory failure, endotracheal tube fixation with only thin adhesive tape, orotracheal intubation, and the lack of intravenous sedation.

The third factor is obviously artificial, as it is an obvious prerequisite of unexpected extubation  in the first place. (Betbese et al. 1998)

It was noted that, at the moment of unexpected extubation  over 61% of the patients were showing signs of clinical agitation. This is therefore almost certainly an indication that sedation levels were not sufficiently high. The converse of this argument is this later on in the paper the author quotes that of the 46 occasions when this happened, only 28 were reintubated. The implication here is that the 18 that were not reintubated, presumably were judged not to need further assistance with their breathing and therefore, almost by definition, were oversedated just prior to the moment of unexpected extubation . 

It is worth considering the other two papers quoted above, in passing as they add to our discussion of the issue. The Krinsley (et al 2005) paper has just been published with the results of a fairly substantial cohort of patients (100) who had unexpected extubation and compared them to a control group of 200 patients (all mechanically ventilated)

This paper did not specifically look at the factors that were associated with unexpected extubation, but concerned itself mainly with the factors that were the consequence of unexpected extubation. The authors note that there was a mortality associated with unexpected extubation  of 20% which is at distinct variance to the Boulain study (he cited only one death in the unexpected extubation group). This paper cites a reintubation rate of 56% which approximates to the rate of the Boulain study. 

Interestingly, the author performed multiple logistic regression calculations on the results and found that:

age was the only predictor of the need for reintubation after unexpected extubation and that age and the need for reintubation were the only predictors of mortality after unexpected extubation.

These are results which we have not seen in any other published work. The author  also comments that there is a statistical correlation between the actual event of unexpected extubation and an increase in the length of stay in the ITU but interestingly, there is also a statistical correlation with a reduction in the mortality rate. (Chevron et al 1998)

Further statistical analysis showed that the differences in the mortality rate corresponded with the perceived need for reintubation. The patients who were not judged to need reintubation universally had “remarkably good outcomes”. The paper concludes with the comment that:

It remains incumbent on ITU teams to institute protocols for regular identification of patients ready to be liberated from mechanical ventilation.

The Epstein paper  (Epstien et al 2000), is ostensibly on the same issue of unexpected extubation, but it appears to be much more clinically orientated than the other two. For this reason it certainly merits consideration. The study itself was rather smaller than the Krinsley study, with 75 study  patients and a control cohort of 150. Significantly, in this case, the controls were matched for “acute Physiology and Chronic Health Evaluation II score, presence of comorbid conditions, age, indication for mechanical ventilation, and sex.” This makes for better statistical analysis of the overall results.

The authors here found similar results in terms of the patients who required reintubation after UEX had significantly longer stays in ITU and higher mortality rates.

A significant features of this study is a particularly insightful resume of the situation pertaining to unexpected extubation in which the authors review the published literature (obviously this does not include the Krinsey figures). They point to the fact tha unexpected extubation occurs in 3-16% of mechanically ventilated patients. (Zwillich et al 1999). The authors present the rather pragmatic view that:

Successfully managed unplanned extubation has the potential of improving outcome by shortening the duration of intubation, thereby reducing the patient's exposure to complications of mechanical ventilation.

They also state the obvious corollary to this argument that a failure to tolerate unexpected extubation has the potential to reduce the chances of a good outcome by subjecting the patient  “to the complications of a premature removal of (demonstrably) needed ventilatory support. It should therefore not be a matter of surprise that some studies have shown an increase in mortality in that group of patients who effectively failed and episode of unexpected extubation when directly compared to those who did not need reintubation. (Atkins et al 1997). 

As we have observed with other articles in this review, the authors comment that only limited conclusions can be drawn from the comparison between these two groups simply because most patients who failed an unexpected extubation (and therefore needed reintubation) had been on full ventilatory support and this contrasts to the group who successfully tolerated unexpected extubation  (no reintubation) who were generally those patients who were in the process of weaning trials. 

They follow this up with the eminently sensible suggestions that:

Therefore, the unique impact of unplanned extubation on outcome is better studied by comparison with controls not experiencing unplanned extubation. The majority of previous studies, including the only published case-control analysis, suggest no increase in mortality when comparing patients with and without unplanned extubation.

If we consider the figures obtained in the Boulain (1998) study and analyse then in this way then we find that there is actually no increase in mortality if these two groups are directly compared.

This study shows that the mortality that was reported in the other papers was actually almost independent of the fact of the unexpected extubation and directly statistically related to the severity of the underlying illness, the actual cause of the respiratory failure in the first place and also the presence of any other co-existing morbidity. (Torres, A et al 1995).

The authors also point to the fact that two other recent studies (Epstein et al 1998) and (Esteban et al 1999) have shown that patients who had been reintubated within 12 hours of a planned extubation had actually a lower mortality rate than those who were reintubated later than 12 hours.  

Taking an overview of this paper, the only practical positive outcome that it presents (apart from the demolition of findings in other papers)
Is that a successfully tolerated unexpected extubation reduced the duration of weaning trials but “had no other measurable beneficial effect on outcome”

One of the reasons for presenting the data contained in these last few papers in comparative detail, is that it demonstrated clearly the difficulties encountered in making a sufficiently uncritical appraisal of the data and statistical analysis of the figures presented. If one makes a sufficiently critical analysis of the data and study design then some facts can be seen as virtually unchallengable and others can be seen as seriously flawed. (Christie, J. M. et al 1996), 

A number of papers that we have read in preparation for this review are centred on the development of a clinically applicable scale that can be used to accurately and reproducibly ascertain the level of sedation. This is clearly a fundamental problem in the consideration of the thrust of this review as correlating the amount of sedation given with the length of time spent on a ventilator is of no value at all as the effect of a given amount of sedation on a 30 stone fit man will clearly be considerably less than on a frail 8 stone elderly lady. Equally there is a huge spectrum of sedatives and indeed, sedative cocktails, that are in common current usage. 

This is an equally valid point of consideration as the type or mixture of sedatives is not nearly as important as the degree of sedation that the particular prescription actually produces. In this next section of the review we shall consider papers that are primarily concerned with this particular point – the ability to quantify the degree of sedation produced by any particular dosage regime in any given patient.(Sessler W 2004) 

Many of the papers that we have assessed thus far have used competitively crude tools as a measure of the degree of sedation experienced by a patient. Some groups have been exploring more subtle and easily reproducible methods of determining the degree of sedation.

One eye-catching recent paper (Haenggi et al 2004) considered and investigated the possibility of assessing the degree of sedation by producing evoked potentials with auditory stimuli. This particular study was done using 10 volunteers who agreed to be sedated to clinical levels with a number of different sedatives. The paper itself is both long and technical, but the results can be condensed into the statement:

Our results suggest that long latency auditory evoked potentials provide an objective electrophysiological analogue to the clinical assessment of sedation independent of the sedation regime used. 

The clinical implications of this study are considerable. The authors were able to demonstrate that acoustic stimuli are capable of producing distinct and discrete changes in the electroencephalogram (EEG). These changes can be used without demonstrable harmful effect to monitor the degree of sedation virtually continuously in clinical conditions and independently of the type of drug that is actually being used to produce the sedative level. (Roustan, J.-P et al 2005). 

The authors point out that considerably more work k needs to be done in order to calibrate and fully implement such observations in a clinical setting, but an initial assessment would suggest that there may well be considerable clinical potential for this particular application.

Sadly, the prognostic predictions of the Haenggi paper are not confirmed by a paper from Rundshagen (et al 2002). His group also considered the possibility of using auditory evoked potentials to assess the depth of sedation. They specifically targeted the midlatency auditory evoked potentials (MLAEP) Na Pa & Nb potentials and found them not to be of any clinical significance in assessing the degree of sedation. Obviously this does not negate the findings of the Haenggi group, but simply underlines the specificity of their findings.

It is important to consider this work in the chronological context.  Thornton (et al 1998) also considered the evoked response in the Nb range and were able to conclude only that the abolition of the AER three wave pattern was indicative of the attainment of the level of sedation where auditory awareness is lost

In another article, Pockett S (1999) reviews the situation further and concludes that although Auditory evoked potentials in the midrange may seem to have the potential for assessment of the level of sedation, he believes that work needs to be done in the high and low range of evoked potentials to fully ascertain the  true potential of the method.

Another recently published paper (Roustan et al 2005) takes the points explored here and raises the bar further with the evaluation of a full EEG analysis to determine any correlation with the overall degree of sedation.

The authors point to the fact that there are no truly (or sensitively) reliable clinically based scales to assess the degree of sedation of a patient. 
(De Jong, M. M. J. et al 2005)

This particular trial is based on the fact that EEG (spectral and bispectral analysis) parameters have been calibrated and used in the past in the form of an index to monitor the depth of operative anaesthesia. They also point to the fact that there have been no published attempts to correlate these findings with a similar application relating to the degree of sedation in an ITU. The trial comprised over 160 EEG recordings from 40 patients. All of the patients were sedated with either midazolam alone or a combination of midazolam and morphine.  

The authors set out to attempt to try to correlate any of the possible measurable parameters of the EEG with two of the most well established clinical sedation scales – the Ramsay and Comfort scales

The authors attempted to correlate which of the parameters were directly related with either too light a state of sedation (Ramsay 1 or 2) or too deep a state of sedation (Ramsay 5 or 6). The paper presents, in great detail, the analysis of the parameters and their correlation (or otherwise) with the level of sedation achieved. For our purposes here we will observe that two of the parameters (called ratio10 and SEF 95) were closely related with the level of sedation, and the relationship was marginally better if the two results were added together.  

The results were found to be highly indicative of the degree of sedation in any one individual patient but there was a large degree of interindividual variability. It was also described that the authors found that bispectral evaluation improved the sensitivity over simple spectral analysis. It follows from this that the technique can be used to great effect once it has been calibrated to the individual patient but it is unlikely that one all-encompassing index could be achieved to apply to all patients.

Another paper (Ely et al 2003) considered how to tackle the problem of assessing the depth of sedation in the ITU patient. At present there are a number of different methods (we have already described some) and a number of different scales that can be used to assess sedative levels. The practical difficulty is that it is difficult to interpret the results of one scale in relation to another. The Ely paper set about a direct comparison between several of the commonly used scales and a common measuring point – the Richmond Agitation – Sedation Scale (RASS). The methods and scales compared included:

RASS, Glasgow Coma Scale (GCS), and Ramsay Scale (RS); validity of the RASS correlated with reference standard ratings, assessments of content of consciousness, GCS scores, doses of sedatives and analgesics, and .bispectral electroencephalography.

The study was designed as a prospective cohort study of over 300 patients. The design was quite ingenious as each patient was independently assessed by two nurses, each using one particular assessment tool. In some cases the nurses assessed the same patient using the same tool independently (but blinded to each other) in order to assess interrater reliability.

Again, the statistical analysis presented in the paper is quite formidable and not appropriate to present here but the important overall conclusions were that the RASS gave the best degree of correlation with all of the available indices. The authors felt able to state, at the end of their paper:

The RASS demonstrated excellent interrater reliability and criterion, construct, and face validity. This is the first sedation scale to be validated for its ability to detect changes in sedation status over consecutive days of ICU care, against constructs of level of consciousness and delirium, and correlated with the administered dose of sedative and analgesic medications.

The argument is examined further, in a slightly different direction in the De Wit (et al 2003) paper. These authors performed a similar exercise to the Ely team (above) insofar as they compared the assessments of sedation level in patients who were receiving sedatives both by continuous infusion and also by other (intermittent) means. They looked at the Sedation-Agitation scale and the bispectral index as evaluations of the sedative level. The cohort was only 19 patients and they analysed 80 assessments on those 19 patients. As a general finding, the authors point out that those patients receiving continuous sedation were more deeply sedated than those who received bolus sedation. This is actually the only really practically useful finding in the paper as the general conclusions that the authors reach are: 

Objective and subjective assessments of sedation are highly correlated. Use of continuous infusions is associated with deeper levels of sedation, and patients receiving continuous infusions are more likely to be oversedated. Sedation therapy should be guided by subjective or objective assessment.

Which, in reality, does little more than to simply confirm the results of many other published works on the subject.A more recent paper by Watson & Kane-Gill (2004) also covers effectively the same ground and does not provide any further help in the assessment of the validity of the various scales

If we consider the relevance of the agents used, there are a number of excellent papers on the subject.

There are clearly a number of sedatives that are commonly used in the ITU setting for the sedation of the ventilated patient. They obviously all have the same macro-effect, but are all subtly different in their mode of operation and their side effect profiles. Their use is determined largely by the personal preference of the lead clinician and his experience together with any protocols that may be in force in any one particular ITU.

In our consideration of the length of time patients spend on mechanical ventilation, we should also properly consider the effect that the choice of the sedative agent has on the overall clinical outcome.

To that end we can start with a very recent paper by Arroliga (et al 2005) which considered the effects of sedatives and neuro-muscular blockers (NMBs) on patients who were on mechanical ventilators.

In effect, this study was a meta-analysis of the use of these agents as the entry cohort was enormous (over 5,000 patients).

The first (and probably self evident) result that the study draws is the fact that those patients who were sedated for their mechanical ventilation spent a statistically significantly longer time on both ventilation and weaning periods than those patients who did not receive sedation. They also spent longer in the ITU than those who did not receive sedation. This is not necessarily a fact that one can use as a direct comparison, as there was no attempt to clinically compare the two groups. 

Any experienced clinician will tell you that, in general terms, the patient who requires sedation for ventilation is actually likely to be more seriously ill than the patient who doesn’t. There are a great number of individual statistical findings drawn from this study, many of which are not directly referable to our considerations here, but one comment is worthy of note and it concerns the use of the NMB group. The study found that:

The administration of an NMB was independently related with age, a normal previous functional status, main reason of mechanical ventilation (patients with ARDS received more NMBs), and with patient management (patients requiring permissive hypercapnia, prone position, high level of positive end-expiratory pressure, and high airways pressure). 

The study concluded that the use of sedatives is commonplace in the ITU setting and is associated with a longer duration of mechanical ventilation. NMBs are found to be used in 13% of patients. They are also independently associated with a longer ventilation time, a longer weaning time and a longer stay in the ITU and also a higher mortality.

These findings are largely echoed in the paper by Christensen BV, Thunedborg LP (1999). They carried out a postal survey on the use of NMB, sedatives and analgesics in ITU units. They present a long paper detailing the trends in usage of these agents. The only really significant finding in direct relation to our considerations here is

NMBAs are only used in a few patients. The frequency of use is correlated to the level of ventilatory support required and to the kind of respiratory disease.

It is most important to get these particular results in perspective however, as they do not take independent account of the severity of the reason for the patient’s admission in the first place and this is clearly a huge independent confounding factor. They clearly therefore have only limited use in the search for a good evidence base in these matters.

While we are considering papers on the topic of choice of agent for sedation there is an excellent review (albeit rather dated now) by Barr (et al. 1995) which considers optimising the dosing strategies for various sedative and analgesic agents in the ITU setting. 

The paper makes the very valid point that the pharmacokinetic parameters of most of these agents were evaluated on healthy individuals in bolus or short term administration regimes. This is generally not the main method of administration in an ITU setting. The authors quote the example of lorazepam and fentanyl whose pharmacokinetics differ significantly in these circumstances when compared to the bolus administration. 

The situation is compounded when we consider the fact that many patients in ITU have major organ systems malfunction and that consideration of the plasma half-life and elimination times many bear little resemblance to those times in healthy volunteers. 

The reason that this paper is included in our considerations is mainly due to one paragraph:

Given the uncertainty of resulting plasma concentrations with long-term administration of these medications, the best ways to achieve and maintain optimal levels of sedation and analgesia while minimising the risk of oversedation and side effects are to initiate sedation in an incremental fashion until the desired level of sedation is achieved, then periodically (i.e., once a day) titrate the infusion rate of sedative-hypnotics and opioids downward until the patient begins to emerge from the sedative effects of these drugs; and finally gradually increase the infusion rate until the desired level of sedation is once again achieved; and consider the use of a sedation scale to standardise the level of sedation to be maintained.

Given the fact that this paper is not ten years old, it provides a useful insight into perhaps part of the rationale behind the considerations in this review. This type of dosage regime is perhaps part of the reason that many of the papers that we have looked at, find that patients tend to be oversedated when on a ventilator, and that utilising different methods and techniques of effectively reducing sedative levels, will reduce the overall length of time that they need to be on a mechanically assisted by a ventilator. 

There is little point in considering this paper further as it is presented here mainly for consideration of these two major factors. Most of the rest of the information contained would now be considered rather outdated. So we shall not consider it further.

A paper which has been used in support of previous statements (above) is the paper by Kollef (et al 1998). This particular paper takes a rather less subtle approach than the other papers that we have considered thus far. (Hong, J. J et al 2000).

Again, the objective of the study is to determine whether the method of administration of sedation is a determinant of the length of time that a patient remains on mechanical ventilation. The nature of the study is a prospective observational cohort study of nearly 250 patients. 

The study differential between the groups was that one group was given sedation by continuous infusion and the other was given their sedation by intermittent bolus injection. In short, the authors were able to conclude from their data that the patients who were receiving their sedation by the continuous infusion method were ventilated for longer (148 hours average) than those who received the bolus sedation (78 hours average). The authors did not venture to express an opinion as to why these differences should be, neither did they present any results relating to the possible adverse effects that may have been experienced by either group. (Tobin et al 2001)

On the face of it however, they seem to have documented a very significant reduction in the length of time that a patient needs to be ventilated simply by administering the sedation in bolus form. The authors appear to support that view as they do not present any counter arguments.

The facts of the matter are however, that there are very serious methodological issues which appear to exert a very significant bias on the results, which the authors notably either overlook or simply fail to present. These sources of bias are fairly obvious on careful, critical assessment of the paper and therefore we will spend some time examining them in some detail, but they are concisely outlined in the next paper that we shall present.

In the interests of critical analysis we should report on the paper by Stefir (et al 1999) which comments on the construction of the Kollef paper. It makes comments in the form of a letter to the editor of “Chest”. Their letter passes comment on the structure of the paper which is not apparent. They start with the suitably abrupt comment:

In the article published in the August 1998 issue of CHEST, Kollef and colleagues came to the conclusion that continuous IV sedation is associated with prolongation of mechanical ventilation. We do not agree with that conclusion.

They base their disagreement on the characteristics of the study groups. We have already noted that this was not a randomised trial and the fact is that the patients in the continuous sedation group had a significantly greater number acute lung injury (or ARDS) and in addition their PaO2/FiO2 ratio was actually considerably lower than those patients in the bolus group.  When the authors therefore present the apparent result that the bolus group spent less time on a ventilator and also less time in the ITU, it is actually far more likely that the prime reason for this was the fact that the patients who stayed longer were actually much more seriously ill than the group that were treated with bolus sedation.

This underlines the need for a thoroughly critical appraisal of each paper. On a brief examination Kollef  and his colleagues appear to have made a fundamental discovery. They notably draw back from publishing overt conclusions about the relationship between bolus and continuous sedation, but the casual reader could be lead to believe that this was the only significant difference between the groups, whereas, in reality there was a very significant element of bias in the trial between the two groups. It would, on careful consideration of the evidence, be safe to conclude that the Kollef paper is neither reliable nor a suitable paper to include in any evidence base for decision making.

Stefir and his colleagues also come up with a number of other very valid criticisms including the very relevant point that the authors did not present any statistical analysis of the actual amount of sedation that either group actually received. In consideration of the point made above, different patients will respond differently to different amounts and types of sedation. Equally, patients who are in need of ventilation in an ITU will probably be suffering from a number of comorbidities, some of which may also affect the way in which the sedative agent exerts its pharmacokinetic profile.  

They also point to the fact that the groups statistics are suspect as their linear regression model did not make any allowance for the degree of lung injury in any of the patients. Quite clearly, both of these factors are extremely relevant in assessing the amount of time that each patient will spend on ventilation and sedation. 

Stefir et al conclude their assessment with a statement in surprisingly
blunt language considering the normal tone of academic journal writing:-

We conclude that the observed differences in the duration of mechanical ventilation may be entirely related to the fact that the continuous IV sedation group had worse lung injury and received more long-acting sedatives than the bolus IV sedation groups and may have nothing to do with the way sedatives were administered.

Notwithstanding any of the above comments we must also report the reaction to the Kollef paper in a different direction. Hersch (et al 1999) wrote a reactionary letter in response to the article by Kollef, which made a different but far more clinically valid objection than did the Stefir article.

Hersch makes the point that patients with a neuromuscular blockade  are clinically an entirely separate group and should therefore not be assessed with the same criteria as the continuous sedation group simply by virtue of the fact that patients with neuromuscular blockade  must have continuous and more profound levels of sedation than those who may be on a bolus regime. The other potentially confounding issue is that it is a matter of common clinical experience that patients who have been given neuromuscular blocking agents are technically very much more difficult to wean off the mechanical ventilation systems (Garland  A 2005)  – all the more so if they have been receiving concurrent steroids at the same time. (Dasta et al 1994)

This represents another major methodological error. It is clinically likely that as there was no proper randomisation in the Kollef trial, it is likely that the patients with neuromuscular blockade  were automatically included in the continuous infusion leg of the trial as they would not have been suitable for the bolus regime of management.

The clinical aspect of this letter comes to the fore in the paragraph

The emotional editorial comment is very moving, but far from being practical or realistic. In our opinion, it is much more inhuman to maintain these patients conscious and aware of their traumatising ICU experience, rather than to optimally sedate them. The use of continuous sedation avoids breakthrough discomfort and pain, as well as unnecessary extubations or line dislodgments, and it also induces "blessed" amnesia. The luxury of 1:1 nurse : patient ratio is not possible in many ICUs; the nurse has really no time for long "sedative" talks with her two patients. However, the patients benefit from the tranquillising effects of the drugs, which also prevent many unwarranted accidents caused by patients' restlessness and the inability of one nurse to adequately control two patients at once, even at the price of a longer weaning period

One has to suggest that any experienced clinician would instinctively agree with these comments both as a clinician and also as a potential patient. (Burns, S. M. 2005). 

In all of our discussions regarding the relationship of mechanical ventilation and the level of sedation we have been (predictably) looking at the situation where a patient is being weaned off a ventilator. There is another type of situation involving these two parameters that commonly occurs in an ITU and that is the cessation of ventilation because the judgement has been made that the patient will not recover. (Green, T et al 2005). In these circumstances it is common practice to increase the levels of sedation  towards the terminal event. (Way et al 2002)

Clearly it is inappropriate to fully discuss all of the issues relating to the termination of life support, but the Way paper is an excellent overview of many of the issues involved. We shall restrict our discussion here however, to those issues relating to sedation and ventilation

Part of the dilemmas faced by clinicians in these specific circumstances are that they may well be reluctant to increase the levels of sedation for fear of the accusation that they may be artificially hastening death. (Ferrand E et al 2001) 

This is actually contrary to the guidelines (Truog et al 2001) which currently recommend that great consideration is given to the avoidance of pain or unnecessary agitation or distress. The guidelines specifically recommend:

Using a combination of morphine or other narcotic with a benzodiazepine, continually infused and titrated until the patient stops showing expressions of discomfort, including grimacing, agitated behaviour, and autonomic hyperactivity. Specific circumstances may also justify the use of barbiturates, haloperidol, or propofol   
(Wilson WC et al 1992) 

The comments with regard to terminating the process of mechanical ventilation are also instructive and are worth considering verbatim:

Mechanical ventilation is one of the few life support treatments that often cannot be stopped abruptly. The common approach to stopping ventilation (often called rapid terminal weaning) is gradually to reduce the fractional inspired oxygen concentration to room air and ventilatory support to zero with anticipatory dosing of narcotics as needed for patient comfort. The patient is then placed on a T-piece with humidified air or extubated. Since the term "weaning" suggests the goal is independent spontaneous ventilation, we prefer the phrase "terminal ventilator discontinuation."

This situation is clearly completely contrary to all that we have discussed thus far, in so far as we are considering the option of increasing sedation in order to reduce the dependency on mechanical ventilation. Such measures are still very worthy of our consideration as we would hope, in this particular situation (as with any other), to be able to make a proper evidence-based decision which we perceive to be in the best interests of the patient. (Prendergast TJ et al. 1998) 

There is one other relevant consideration in this section and that is the subject that we have discussed at length earlier, and that is the topic of neuromuscular blockade . It is a common belief that neuromuscular blocking drugs may well ease the family’s distress by giving the appearance that their relative is completely undisturbed and peaceful. (Covinsky KE et al. 2000)

There is the possibility that they may theoretically increase the discomfort experienced by the patient  by virtue of the fact that clinicians cannot adequately assess the degree of patient discomfort when a full neuromuscular blockade is present. (Breen CM et al 2001)

The current recommendations are that paralytic drugs should be withdrawn before the life sustaining therapies are withdrawn to allow time for the drug to be eliminated from the body. (Faber-Langendoen et al 1996)

For most of this piece we have restricted our discussion to specifically the adult population. This, of course, completely overlooks that fact that children also are in need of ITU ventilation and other services. We shall conclude by examining some of the papers that relate to sedation and ventilation issues in paediatric practice.

One interesting discussion point is the one raised by Rashid (et al 2000)

He points to the fact that in cases of neonatal intubation it is common not to use analgesia as it is widely believed that the perception of pain by the baby is not recalled and can be relieved by measures such as glucose  (Carbaial R et al 1999). He also points to the fact that it is comparatively common practice in the UK not to use sedation for the intubation procedure and this is contrasted to the common practice in the USA and Australia where sedation is almost universally used. (Levene MI et al 1997)

Rashid points to evidence that it can be demonstrated that the neonate can produce spikes of systolic blood pressure and intracranial pressure during painful procedures even when they have been paralysed indicating the effect of pain and distress (Charlton AJ et al 1998). He therefore makes the case for adequate sedation during both the intubation and the mechanical ventilation procedures.

There is also an interesting comment on this topic in the form of a comment by Bhutada (et al 2000) who points to the fact that not only should there be adequate sedation given in these circumstances but also there should be adequate premedication prior to the procedure for the same reasons.

We have presented here a substantial overview of much of the currently available literature which has a bearing on the issues of sedation and mechanical ventilation. Much of it is carefully written and executed, but, as we have demonstrated, there is a substantial proportion that is flawed and requires careful assessment.

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