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Hyperglycaemia after acute stroke

BMJ 1997; 315 doi: https://doi.org/10.1136/bmj.315.7111.810 (Published 27 September 1997) Cite this as: BMJ 1997;315:810

Other models find that hyperglycaemia is not independent predictor

  1. Carl Counsell, Clinical research fellowa,
  2. Mike McDowall, Programmera,
  3. Martin Dennis, Senior lecturer in stroke medicinea
  1. Department of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU
  2. b Addenbrooke's Hospital, Cambridge CB2 2QQ
  3. c University of Newcastle, School of Clinical Medical Sciences, Department of Medicine for the Elderly, Sunderland Royal Hospital, Sunderland SR4 7TP
  4. d Acute Stroke Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT
  5. e Medical Statistics Unit, Medical School, University of Edinburgh, Edinburgh EH8 9AG

    Editor—Christopher J Weir and colleagues conclude from their study of a cohort of 750 non-diabetic patients with stroke that hyperglycaemia (plasma glucose concentration >8 mmol/l) during the acute phase has an adverse influence on outcome and that this is independent of severity of stroke.1 Stroke severity was assessed in a limited way using only the Oxfordshire community stroke project classification and time to resolution of symptoms (≤72 hours or >72 hours), both of which are relatively inaccurate measures. When two variables are closely correlated—for example, stroke severity and glucose concentration—the one that is most accurately measured (glucose concentration) will always emerge as the strongest explanatory variable in multiple regression even if it is, in fact, less important.2

    We have produced a series of validated models to predict the probability of survival and disability using the 530 patients from the Oxfordshire community stroke project who were seen within 30 days of their stroke.3 A history of diabetes mellitus and the presence of acute hyperglycaemia (glucose concentration >12 mmol/l) were two of about 20 variables that were entered into these models, in addition to several measures related to stroke severity (eye, motor, and verbal components of the Glasgow coma score; arm power; and ability to walk). Although diabetes mellitus was an adverse and independent predictor of death (relative hazard 2.01; 95% confidence interval 1.36 to 2.99), hyperglycaemia was not (1.66; 0.93 to 2.97). Neither of these variables was an independent predictor of death or disability (modified Rankin score >2) at six months.

    We repeated our analyses using only the 249 patients seen within 72 hours of onset with no known history of diabetes; we redefined hyperglycaemia as glucose concentration >8mmol/l to allow direct comparison with the results of Weir and colleagues. Once more, hyperglycaemia was not an independent predictor of either death (relative hazard 1.02; 0.62 to 1.66) or death or disability (odds ratio 1.61; 0.38 to 6.75).

    We would therefore disagree that hyperglycaemia is an independent prognostic factor in acute stroke. We would, however, agree that a large randomised trial of glucose control in the acute phase of stroke is necessary to clarify the clinical management of these patients. Many guidelines recommend that hyperglycaemia should be treated aggressively with insulin infusions4; we are not aware of a single completed randomised trial addressing this issue, and so it remains unclear whether the risks of such an approach—for example, hypoglycaemia—outweigh any possible benefits.

    References

    1. 1.
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    4. 4.

    May occur as result of neuroendocrine response

    1. Alex Mitchell, Senior house officer in psychiatryb,
    2. Peter Kirckpatrick, Consultant in neurosurgeryb
    1. Department of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU
    2. b Addenbrooke's Hospital, Cambridge CB2 2QQ
    3. c University of Newcastle, School of Clinical Medical Sciences, Department of Medicine for the Elderly, Sunderland Royal Hospital, Sunderland SR4 7TP
    4. d Acute Stroke Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT
    5. e Medical Statistics Unit, Medical School, University of Edinburgh, Edinburgh EH8 9AG

      Editor—In the largest study of its kind to date, Christopher J Weir and colleagues report that early hyperglycaemia predicts mortality after stroke.1. This investigation confirms similar findings from our group and others. The authors suggest, however, that a raised plasma glucose concentration “is not solely a stress response to neurological insult, as it predicts outcome after taking other prognostic factors into account.” This conclusion is unfounded. An association, even a causative one, between glucose concentration and poor recovery does not exclude the possibility that the hyperglycaemia occurs as a result of a neuroendocrine stress response. Indeed, many measures of this stress hormone response have been correlated with poor outcome in stroke as well as in other critical illnesses.2 Cortisol, one of the core regulators of both the stress response and plasma glucose concentration, is directly neurotoxic and inhibits recovery after brain injury.3

      Several findings suggest that hyperglycaemia after stroke is related to stress, albeit it has prognostic effects.4 Firstly, hyperglycaemia correlates with lesion size in most studies. Secondly, hyperglycaemia closely correlates with increases in other stress hormones. Thirdly, the rise and fall of glucose concentrations after stroke parallels the classic neuroendocrine release profile. The physiological association between concentrations of plasma glucose and blood pressure at admission is indirect at best. Therefore, the moderate statistical correlation between these two variables shown by Weir and colleagues is not surprising and certainly not evidence against a glucose response related to stress. As discussed in the paper, a correlation between early haemoglobin A1c concentration and poor outcome shown by some studies is evidence that hyperglycaemia before stroke is important. This correlation, however, is much less important than the correlation with glucose concentrations after stroke, even in diabetic patients.

      This clarification is not just of academic interest. Hyperglycaemia after stroke is certainly associated with poor outcome, but does it contribute to it? The authors believe that plasma glucose concentration is an independent predictor of prognosis after age, stroke type, and stroke severity have been controlled for, but they do not control for stress hormones, which are themselves related to both glucose and outcome after stroke. It may well transpire that reduction of hyperglycaemia—short of inducing hypoglycaemia—may be helpful after stroke, but, equally, the therapeutic potential of antiglucocorticoids should be investigated.

      References

      1. 1.
      2. 2.
      3. 3.
      4. 4.

      Participants required for trial of treatment with glucose and insulin

      1. Jonathan Scott, Medical registrarc,
      2. Janice O'Connell, Senior lecturerc,
      3. Christopher Gray, Professorc
      1. Department of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU
      2. b Addenbrooke's Hospital, Cambridge CB2 2QQ
      3. c University of Newcastle, School of Clinical Medical Sciences, Department of Medicine for the Elderly, Sunderland Royal Hospital, Sunderland SR4 7TP
      4. d Acute Stroke Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT
      5. e Medical Statistics Unit, Medical School, University of Edinburgh, Edinburgh EH8 9AG

        Editor—The results of the study by Christopher J Weir and colleagues on the prognostic importance of hyperglycaemia after acute stroke correspond with previous work done in Newcastle.1 2 In our study, hyperglycaemia (blood glucose concentration >8 mmol/l) was detected in 22.8% of 200 consecutive patients with acute stroke and was associatexd with significantly increased mortality at four and 12 weeks; only nine of the 31 hyperglycaemic patients had a history of diabetes mellitus.2

        Weir and colleagues performed separate analyses of results for known diabetic and non-diabetic patients. The proportion of hyperglycaemic patients was, not surprisingly, lower in the non-diabetic group (22% v 69%). As alluded to in the discussion section of their paper, however, glycated haemoglobin (HbA1c) concentrations were not estimated and therefore some of the subjects in the non-diabetic group probably had diabetes or glucose intolerance which had been unrecognised previously. This is an important omission since hyperglycaemia may have a different effect on outcome in diabetic patients with stroke.3 Furthermore, previous work by our group has shown raised HbA1c concentrations in 33.8% of patients with acute stroke, four fifths of whom had no known history of diabetes.2 A raised HbA1c concentration >7.5% was a significant predictor of death in older patients and was likely to be associated with raised plasma glucose concentrations on admission.

        There is growing evidence from clinical and laboratory studies of the detrimental effect of hyperglycaemia in acute stroke. Studies on animals have shown that coadministration of glucose and insulin at the time of experimentally induced focal ischaemia can reduce cerebral infarction after middle cerebral artery occlusion.4 A recent trial in diabetic patients with myocardial infarction has shown that glucose-insulin treatment reduced mortality.5 The precise time span during which hyperglycaemia occurs after stroke in humans is unknown. Consequently, the window of opportunity during which randomisation to euglycaemic treatment should take place is unclear and will need to be addressed in prospective studies. Furthermore, the safety of euglycaemic control immediately after stroke has not been formally studied in patients with acute stroke. The safety of such an intervention needs to be established before a multicentre randomised clinical trial is conducted.

        We agree with Weir and colleagues that there is sufficient evidence to warrant a study of maintenance of euglycaemia in hyperglycaemic patients after acute stroke. Our group has recently obtained a grant from the Stroke Association to carry out a pilot study of the safety of glucose-insulin treatment in patients with acute stroke. We would be interested to hear from potential collaborators for a multicentre trial of this treatment.

        References

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        Authors'reply

        1. Christopher Weir, MRC training fellowd,
        2. Alexander Dyker, Lecturer in stroke medicined,
        3. Kennedy Lees, Clinical directord,
        4. Gordon Murray, Professor of medical statisticse
        1. Department of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU
        2. b Addenbrooke's Hospital, Cambridge CB2 2QQ
        3. c University of Newcastle, School of Clinical Medical Sciences, Department of Medicine for the Elderly, Sunderland Royal Hospital, Sunderland SR4 7TP
        4. d Acute Stroke Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT
        5. e Medical Statistics Unit, Medical School, University of Edinburgh, Edinburgh EH8 9AG

          Editor—The suggestion by Carl Counsell and colleagues that the severity of stroke and plasma glucose concentration are closely correlated is not confirmed by our findings. There was only a weak correlation (r=0.14, P<0.01; n=295) between scores on the National Institutes of Health stroke scale and plasma glucose concentrations in our patients. Contrary to their statement regarding accuracy of measurement, if two strongly correlated variables were included in a multiple regression neither would have a significant independent effect. The results of the models produced by Counsell and colleagues to study the relation between hyperglycaemia and outcome in acute stroke are consistent with ours since there is a considerable overlap with our confidence intervals, both for relative hazard of death and for odds ratio of death or dependency.

          A large randomised trial of glucose control in hyperglycaemic patients with acute stroke is essential. Exacerbation of infarction by hyperglycaemia after experimentally induced ischaemia was discussed in our paper. The theoretical arguments concerning cause and effect presented by Alex Mitchell and Peter Kirckpatrick are less important than the question about the clinical management of hyperglycaemia, which will be answered by the results of a clinical trial. We are pleased to note that Jonathon Scott and colleagues are performing a pilot study of glucose control in acute stroke. We are piloting a similar study and have initiated discussion with several British and international investigators to plan a multicentre trial

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