Abstract
Objective: To investigate the effectiveness of maintaining blood glucose levels below 6.1 mmol/L with insulin as prevention of secondary injury to the central and peripheral nervous systems of intensive care patients.
Methods: The authors studied the effect of intensive insulin therapy on critical illness polyneuropathy (CIPNP), assessed by weekly EMG screening, and its impact on mechanical ventilation dependency, as a prospectively planned subanalysis of a large randomized, controlled trial of 1,548 intensive care patients. In the 63 patients admitted with isolated brain injury, the authors studied the impact of insulin therapy on intracranial pressure, diabetes insipidus, seizures, and long-term rehabilitation at 6 and 12 months follow-up.
Results: Intensive insulin therapy reduced ventilation dependency (p = 0.0007; Mantel–Cox log rank test) and the risk of CIPNP (p < 0.0001). The risk of CIPNP among the 405 long-stay (≥7 days in intensive care unit) patients was lowered by 49% (p < 0.0001). Of all metabolic and clinical effects of insulin therapy, and corrected for known risk factors, the level of glycemic control independently explained this benefit (OR for CIPNP 1.26 [1.09 to 1.46] per mmol blood glucose, p = 0.002). In turn, prevention of CIPNP explained the ability of intensive insulin therapy to reduce the risk of prolonged mechanical ventilation (OR 3.75 [1.49 to 9.39], p = 0.005). In isolated brain injury patients, intensive insulin therapy reduced mean (p = 0.003) and maximal (p < 0.0001) intracranial pressure while identical cerebral perfusion pressures were obtained with eightfold less vasopressors (p = 0.01). Seizures (p < 0.0001) and diabetes insipidus (p = 0.06) occurred less frequently. At 12 months follow-up, more brain-injured survivors in the intensive insulin group were able to care for most of their own needs (p = 0.05).
Conclusions: Preventing even moderate hyperglycemia with insulin during intensive care protected the central and peripheral nervous systems, with clinical consequences such as shortening of intensive care dependency and possibly better long-term rehabilitation.
Patients admitted to intensive care, even for reasons other than primary brain injury, often develop a secondary type of injury to the nervous system. Besides a reversible and not well understood diffuse encephalopathy, predominantly associated with the systemic inflammatory response syndrome (SIRS) and sepsis,1 this secondary injury also affects the peripheral nervous system. Critical illness polyneuropathy (CIPNP) occurs in up to 70% of patients in the intensive care unit (ICU) with SIRS or sepsis.2–4 Although clinical signs are initially absent or undetected, CIPNP may cause skeletal muscle weakness or even paralysis. EMG is required for the diagnosis3 and reveals primary axonal degeneration of first motor and then sensory neural fibers, which accords with microscopic signs of acute and chronic denervation in muscle biopsies. If the underlying condition can be successfully treated, recovery usually ensues. Risk factors include the use of neuromuscular blocking agents and glucocorticoids,5,6 aminoglycoside antibiotics,7,8 vasopressors,9,10 parenteral nutrition,5 and renal replacement therapy.9 All these risk factors are integrally related to sepsis and severity of illness and thus their causal relationship to CIPNP is unclear. As for the critical illness-associated encephalopathy, the exact pathophysiology of CIPNP remains largely unknown.
Hyperglycemia at the time of brain injury such as ischemic stroke, cerebral hemorrhage, or cerebral trauma is long known to be associated with increased morbidity and mortality.11–13
It remains controversial as to whether this association merely reflects the severity of the primary injury or hyperglycemia acts as a secondary insult onto the nervous system that is contributing to worse outcome. Recently, persistence of hyperglycemia during the poststroke episode was found to be independently associated with infarct expansion and adverse outcome.14 However, to date, no clinical intervention study has addressed the question of a causal relationship between hyperglycemia and clinical outcome of stroke or cerebral trauma.
In the current study, we investigated the role of hyperglycemia during intensive care as a secondary insult on both central and peripheral nervous systems of critically ill patients.
Methods.
This study is a preplanned subanalysis of a large (n = 1,548) prospective, randomized, controlled trial on the effects of intensive insulin therapy on outcome of critical illness.9 The detailed protocol of the study and the characteristics of the patients have been previously published.9
All mechanically ventilated adult patients admitted to a mainly surgical ICU were eligible for inclusion (see appendix E-1 on the Neurology Web site at www.neurology.org). After stratification for reason for ICU admission, patients were randomized to either strict glycemic control below 6.1 mmol/L (110 mg/dL) with intensive insulin therapy or to the conventional approach, which only recommended insulin therapy when blood glucose levels exceeded 12 mmol/L (220 mg/dL).
Outcome measures.
The primary outcome measure for all patients in this study included death from any cause during intensive care, CIPNP, and days on the ventilator (see appendix E-2). The presence of CIPNP was prospectively assessed electromyographically in all 405 patients still in ICU on day 7 (table 1), and subsequently on a weekly (±1 day) basis by one electrophysiologist who was unaware of the treatment assignments. This weekly electrophysiologic investigation comprised a needle EMG of proximal and distal muscles in both upper and lower extremities. The diagnosis of CIPNP was based exclusively on the presence of abundant spontaneous activity in the form of positive sharp waves and fibrillation potentials. CIPNP was diagnosed only when these EMG abnormalities were present in multiple distal and proximal muscles in all extremities. Muscles innervated by nerves susceptible to pressure palsies were avoided. Myopathy could not be diagnosed electromyographically, as patients were often either not cooperative or unconscious. Furthermore, because of pronounced weakness of long-stay ICU patients, motor unit action potentials are often unrecruitable. The impact of intensive insulin therapy on CIPNP, the need for mechanical ventilation, and the interdependence between these two hazards was assessed (see appendix E-3).
Table 1 Baseline characteristics of 405 patients in ICU for 7 days or longer
The primary outcome measures evaluated in the stratified subgroup of 63 patients with isolated brain injury (table 2) included intracranial pressure relative to cerebral perfusion pressure and CSF drainage, diabetes insipidus, seizures, and the proportion of patients attaining a Karnofsky Performance Score15 of 60% or greater as determined by masked investigators at 6 and 12 months post hospital discharge (see appendix E-4).
Table 2 ICU patients with isolated brain injury at baseline
Statistical analysis.
Normally distributed data were presented as means ± SD and skewed data as medians and interquartile range (IQR), unless indicated otherwise. The effect of intensive insulin therapy on the time course of 1) weaning from mechanical ventilation and 2) occurrence of CIPNP was assessed by Kaplan–Meier analysis (Mantel–Cox log-rank test). The assessment of time on the ventilator was right censored for early deaths and the analysis of time until CIPNP was censored for “not being EMG screened because no longer in ICU on day 7.” Patients who left the ICU negative for CIPNP were considered negative thereafter.
Other differences between study groups were analyzed by χ2 test, unpaired Student t test, and Mann–Whitney U test, when appropriate. Bonferroni correction was applied for multiple testing in time. Paired comparisons were performed using Wilcoxon signed rank test. Spearman (rho) correlation coefficients were calculated for quantifying the relation between variables.
Multivariate logistic regression analysis was performed to understand the effect of intensive insulin therapy on CIPNP and for assessing the impact of CIPNP on the need for prolonged mechanical ventilation (see appendix E-5).
Results.
Intensive insulin therapy reduced the risk of developing CIPNP and thereby reduced the time on mechanical ventilation.
The 783 patients randomized to conventional insulin therapy and the 765 patients randomized to intensive insulin therapy were comparable at baseline.9 Table 1 shows that the two groups of long-stay (7 days or longer and screened with EMG for CIPNP) ICU patients, randomized to conventional or intensive insulin therapy, were also comparable at ICU admission. Also, as previously published in the total study population, in the subgroup of long-stayers who were screened for CIPNP, intensive insulin therapy reduced ICU mortality from 21% to 12% (p = 0.01), ICU stay from a median (IQR) of 15 (11 to 28) to 14 (9 to 24) days (p = 0.02), acute renal failure from 26% to 17% (p = 0.02), bacteremia from 26% to 17% (p = 0.02), and time on antibiotics from 12 (7 to 21) to 10 (7 to 16) days (p = 0.008). The mean blood glucose level in the intensive insulin treated long-stay patients was 5.6 ± 0.5 mmol/L vs 8.4 ± 1.7 mmol/L in the conventionally treated patients (p < 0.0001).
Figure 1 shows that in the total study population, intensive insulin therapy increased the cumulative chance over time for being weaned from mechanical ventilation (see figure 1, upper panel) and reduced the cumulative risk over time for developing CIPNP (see figure 1, lower panel). The upper Kaplan–Meier cumulative hazard plot indicates that the largest effect on mechanical ventilation requirement occurs after 14 days. Hence, mechanical ventilation dependency after that time was considered prolonged. Intensive insulin also reduced the incidence of CIPNP and the need for prolonged (>14 days) mechanical ventilation among the long-stayers (at least 7 days in ICU and thus screened by EMG) (table 3), whereas there was no difference in the use of glucocorticoids, aminoglycoside antibiotics, or muscle relaxants, substances that are known risk factors for CIPNP.
Figure 1. Kaplan–Meier cumulative hazard plots for time to weaning from ventilator and time to the first positive EMG for critical illness polyneuropathy (CIPNP). The cumulative hazard plot in the upper panel shows that in the entire study population (n = 1,548), intensive insulin therapy (open circles) reduced the time until weaning from the ventilator as compared with conventional insulin therapy (filled circles). The Cox-regression model was right-censored for early deaths. The cumulative hazard plot in the lower panel shows that in the entire study population (n = 1,548), intensive insulin therapy reduced the risk for CIPNP, as assessed by weekly EMG screenings. The model was right-censored for those patients who were not screened by EMG because no longer in intensive care unit (ICU) on day 7. Patients who left the ICU negative for CIPNP were considered negative thereafter. p Values were determined with use of the Mantel–Cox log-rank test.
Table 3 Effects on CIPNP and mechanical ventilation in 405 patients in ICU for 7 days or longer
Multivariate logistic regression analysis (see appendix A-6 and table E-1), correcting for known risk factors including duration of ICU stay, the use of vasopressors, muscle relaxants, glucocorticoids, or aminoglycosides, and other comorbidities such as acute renal failure, sepsis, inflammation, and dyslipidemia (see figure E-1), revealed that the level of blood glucose control (see appendix E-7) but not the insulin dose (see figures E-1 and E-2) independently explained the reduced risk of CIPNP with intensive insulin therapy (OR 1.26, 95% CI 1.09 to 1.46 per mmol blood glucose; p = 0.002). Similarly, logistic regression analysis demonstrated that the reduced risk of CIPNP independently explained the reduced risk of prolonged mechanical ventilation with intensive insulin therapy (OR 3.75, 95% CI 1.49 to 9.39; p = 0.005) (see appendix E-7 and table E-2).
Intensive insulin therapy protected the CNS in ICU patients with isolated brain injury.
The subgroups of 63 ICU patients with isolated brain injury randomized to conventional or intensive insulin therapy were comparable at ICU admission (see table 2 and appendix E-8). The incidence of hypoglycemia in this group of patients with brain injury was not higher with intensive insulin therapy (12.1%) vs the conventional approach (3.3%, p = 0.2).
In contrast to what we observed in the total study population9 and in the 405 patients in ICU for 7 days or longer (see table 1), in this small subgroup of patients with isolated brain injury, ICU mortality (23% in the conventional group vs 18% in the intensive insulin group, p = 0.6) was not affected by the intervention. Also, hospital mortality (30% vs 36%, p = 0.6) and the mortality at 6 months (30% vs 48%, p = 0.3) and 12 months (30% vs 51%, p = 0.2) after hospital discharge was not different.
The non-neurologic intensive care morbidity was reduced as evidenced by a substantially reduced duration of mechanical ventilation (from a median [IQR] of 15 [12 to 25] to 7 [4 to 13] days, p = 0.0007), ICU stay (from 16 [12 to 28] to 7 [4 to 14] days, p = 0.002), and hospital stay (from 43 [22 to 100] to 31 [13 to 60] days, p = 0.05), and reduced incidence of bloodstream infections, antibiotic therapy, and excessive inflammation. Twenty-seven percent of patients in each group were treated with glucocorticoids.
Intensive insulin therapy clearly protected the CNS as evidenced by lower levels of peak and mean intracranial pressures despite similar perfusion pressures that were reached with eightfold less vasopressors and despite similar amounts of CSF drainage (table 4). Incidence of diabetes insipidus tended to be lower and seizures were less frequent with intensive insulin therapy as compared with the conventional approach (see table 4).
Table 4 Effects on the CNS of patients with isolated brain injury
Intensive insulin therapy improved long-term rehabilitation of ICU patients with isolated brain injury.
ICU patients with isolated brain injury left the hospital in a similar state of severe disablement as evidenced by the low Karnofsky scores (figure 2). Karnofsky scores increased with time in both groups’ survivors, but the score increased further between 6 and 12 months only in the intensive insulin group with no change in the conventional group (see figure 2). Hence, the fraction of survivors who were able to care for most of their own needs (Karnofsky score of ≥ 60) at 12 months was significantly higher in the intensive insulin group (see table 4).
Figure 2. Long-term rehabilitation of patients surviving isolated brain injury. Karnofsky performance scores (%) (medians and interquartile ranges) at 6 and 12 months in the intensive care unit patients with isolated brain injury who survived the hospital stay. Unpaired comparisons were done using Mann–Whitney U test and the paired comparisons by Wilcoxon signed rank test. The data indicate that Karnofsky scores increased with time in both groups, but the score increased further between 6 and 12 months only in the intensive insulin group with no change in the conventional group.
Discussion.
Intensive insulin therapy prevented secondary injury onto the peripheral and central nervous systems as evidenced by the reduced incidence of CIPNP and hence ventilator dependency in a variety of surgical ICU patients and by lower intracranial pressure, less seizures, and a better long-term rehabilitation of ICU patients with isolated brain injury.
Intensive insulin therapy to avoid even moderate hyperglycemia during intensive care appeared to be highly protective for the peripheral nervous system of critically ill patients as it significantly reduced the incidence of CIPNP. There was no difference in the use of glucocorticoids and aminoglycosides, and thus these iatrogenic factors did not affect the observation. The preventive effect of intensive insulin therapy on occurrence of CIPNP was statistically explained exclusively by its effect on blood glucose control. It is hitherto unclear how preventing direct glucose toxicity explains this acute neuroprotection. However, we recently showed that hyperglycemia induces mitochondrial dysfunction and ultrastructural damage in hepatocytes of critically ill patients, which is prevented by intensive insulin therapy.16 Since apoptosis and oxidant injury have been suggested to play a role in causing CIPNP,17 one could speculate that a similar protective effect on the neuronal mitochondria by intensive insulin therapy is involved in the prevention of CIPNP. The reduced incidence of CIPNP in turn independently explained the reduced requirement of mechanical ventilation, which was obtained with intensive insulin therapy in these long-stay ICU patients (see appendix E-9).
Intensive insulin therapy also protected the CNS, as it reduced mean and maximal intracranial pressure in patients with isolated brain injury. This beneficial effect on intracranial pressure occurred in the presence of similar cerebral perfusion pressures that were achieved with significantly less norepinephrine as a vasopressor. This is the first randomized controlled study providing evidence for an effective metabolic measure to prevent secondary insults after brain injury. The beneficial effect of intensive insulin therapy on intracranial pressure coincided with clinical correlates thereof such as less seizures and a trend for less diabetes insipidus. The finding that similar cerebral perfusion pressures were obtained with less vasopressors (lower doses and for a shorter time) in the face of lower intracranial pressures suggests a direct effect of intensive insulin therapy on the CNS. The absence of an effect on the amount of drained CSF suggests that this CNS protection is directed toward the neural cells. There are several potential mechanisms involved, including prevention of glucose toxicity as well as direct effects of insulin independent of glycemic control (see appendix E-10).
There also appeared to be a long-term benefit of intensive insulin therapy during intensive care as a larger fraction of survivors after isolated brain injury rehabilitated to a level of independent living after 12 months. Although the sample size of our study was small, the clinical relevance of this observation, if confirmed in a larger study, is enormous.
The current study has some strong and some weak points. The prospective, randomized, controlled nature of the study and the large sample size is a strong point. Furthermore, the effect of the intervention on CIPNP was shown in a large group of patients, studied prospectively with systematic EMGs from day 7 onward by one dedicated and blinded electrophysiologist, the latter minimizing inter- and intrarater variability in the diagnosis of CIPNP. In addition, the study relates the reduced incidence of EMG-diagnosed CIPNP with intensive insulin therapy to clinically relevant consequences such as prolonged mechanical ventilation. This relationship took all previously known risk factors into the equation. A strength of the study on the effects on the CNS is the unique opportunity to study the CNS effects in human subjects via the ICP catheter. The inevitable nonblinded nature of the insulin titration was a weakness. However, since the titration of insulin was performed by the nursing team and supervised by a study physician, who were not involved in diagnostic or therapeutic decision making, and since data entry was done by independent investigators who took all necessary precautions to guarantee blinding of the insulin therapy, bias was minimized. Another weakness of this study of the intensive insulin therapy impact on long-term rehabilitation is the small sample size of patients with isolated brain injury, which clearly requires confirmation in a larger sample. Finally, the single center nature of the study limits extrapolation to other settings.18,19
Acknowledgment
The authors thank Ilse Milants, Jenny Gielens, An Andries, and Myriam Vandenbergh for data entry, the clinical fellows of the Department of Physical Medicine and Rehabilitation for help with systematic EMG screening, and the ICU physicians for patient care.
Footnotes
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Editorial, see page 1330
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the April 26 issue to find the title link for this article.
Supported by the Fund for Scientific Research, Flanders, Belgium (G.0278.03), the Research Council of the Catholic University of Leuven (OT 03/56), and the Belgian Foundation for Research in Congenital Heart Diseases. G.V.d.B. is a Fundamental Clinical Research Investigator (G.3C05.95N) for the Fund for Scientific Research, Flanders. G.V.d.B. holds an unrestrictive Catholic University of Leuven Novo Nordisk Chair of Research.
Presented in part at the 16th annual congress of the European Society of Intensive Care Medicine; October 5–8, 2003; Amsterdam, Netherlands; and at the 86th annual meeting of the Endocrine Society; June 16–19, 2004; New Orleans, LA.
Received June 14, 2004. Accepted in final form December 22, 2004.
References
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