Correlation between Intraoperative Serum Lactate and New-Onset Postoperative Neurodeficits in Patients Undergoing Elective Craniotomies.

Background: Elevated lactate levels in neurosurgical patients are seen in brain tumors, traumatic brain-injury, brain infarction, and subarachnoid hemorrhage. Hyperlactatemia during craniotomy may be caused by hypotension due to multiple factors. Recently, intraoperative hyperlactatemia has been associated with fresh-onset neurodeficits. Aims: We studied the prevalence of hyperlactatemia in patients undergoing craniotomy and relationship between intraoperative hyperlactatemia and development of new postoperative neurodeficit. Study Design: Eighty-six patients, American Society of Anesthesiologists Classes I,II and III, undergoing elective craniotomy for neurosurgical indications were included in this prospective, observational study in a tertiary care center. Materials and
Methods: Baseline, intraoperative, and postoperative (upto 12 h) lactate levels were noted. Neurological examination to detect new-onset neurodeficits was done at intervals up to 72 h postoperatively. Lactate levels were compared between patients who developed neurodeficits and those who did not develop neurodeficits postoperatively. Statistical Analysis: Statistical analysis of the correlation between intraoperative hyperlactatemia and fresh postoperative neurodeficit was done using the Chi-square test.
Results: The prevalence of intraoperative hyperlactatemia was found to be 52.3% and that of fresh-onset postoperative neurodeficits was 31.4%. The relationship between the two was statistically insignificant (P > 0.05).
Conclusion: The intraoperative hyperlactatemia is not correlated with the development of fresh-onset postoperative neurodeficit. Implications: There may be no relationship between the intraoperative lactate levels and fresh-onset postoperative neurodeficits. Multifactorial reasons may be responsible for increased lactate levels which need to be identified by further research. Copyright:

INTRODUCTION

Neurosurgical patients have a high risk of neurological complications in the immediate postoperative period increasing both morbidity and mortality.[1] Although nonneurological complications are more common, major neurological complications are also frequent.[2] Cranial procedures are 2.6 times more likely to produce complications (24%) as compared to spinal procedures (11%).[3]

Postoperative neurosurgery patients frequently have significantly elevated serum lactate levels even in the absence of hypotension. Although, at times, elevated serum lactate could be self-limiting and without consequences, in many intracranial procedures increased serum lactate may be present in the postoperative period. For reasons not fully understood, intraoperative serum lactate levels rise markedly and often during craniotomies[45] either through direct cerebral compression or regional metabolic changes. Increase in lactate levels during craniotomies may be due to systemic end-organ hypo-perfusion secondary to fluid deficits, hemorrhage, comorbid medical conditions (sepsis and congestive heart failure), or a combination of these factors.

Neurosurgical procedure often requires an excessive amount of retraction of the brain, resulting in brain damage, which is one of the most common causes of postoperative complications.[6] Clinically, significant postoperative deficits, in general, appear in 3%–9% of cases.[7]

We, therefore, undertook a prospective study to assess the clinical significance of hyperlactatemia in patients undergoing craniotomy and to correlate intraoperative serum lactate levels and fresh-onset neuro-deficits.

We hypothesized that in the craniotomy population, in the absence of systemic causes of hypotension, serum lactate is a marker of early regional hypo-perfusion of the brain and that elevated intraoperative levels are associated with the development of new neurological deficits. If the association is established, then increasing intraoperative serum lactate necessitates intervention or may predict impending poor neurologic outcome.

The aim of this study was to assess the prevalence of hyperlactatemia in patients undergoing craniotomy for various neurosurgical procedures and to study whether intraoperative hyperlactatemia is correlated with the development of a fresh onset neurodeficit in patients who have undergone craniotomy.

MATERIALS AND METHODS

This hospital-based prospective, observational study was conducted over a period of 2 years after obtaining approval from the Institutional Ethical Committee. A written informed consent was taken from the patients or their immediate attendants (for unconscious patients and minors) for participation in this study and use of the patient data for research and educational purposes.

All patients, who underwent elective craniotomies, were enrolled in the study, whereas patients undergoing repeat surgical procedures, cerebrospinal fluid shunt procedures and those with comorbid conditions predisposing them to an intraoperative increase in serum lactate, for example, liver disease, kidney disease, shock, and sepsis were excluded from the study.

After the general preoperative assessment, neurological evaluation was done using Glasgow Coma Scale score and world federation of neurosurgeons grading. Any preexisting neurological deficits were recorded and all the baseline investigations including complete blood count, kidney function test, liver function test, blood glucose, serum electrolytes, electrocardiogram, chest X-ray, besides preoperative baseline lactate levels were recorded in every study subject.

Anesthetic management was performed using a standard protocol. Standard monitors were positioned, general anesthesia was induced with inj. fentanyl 2 μg.kg-1, Inj. xylocard 1.5 mg.kg-1, propofol 2 mg.kg-1, followed by intravenous (i.v.) atracurium 0.5 mg.kg-1 to facilitate endotracheal tube placement. General anesthesia was maintained with isoflurane (1–1.5 volume%), nitrous oxide (60%), and O2(40%). Atracurium was administered, as required, to maintain adequate relaxation. Injection fentanyl 1 μg.kg-1 was given every hour for the maintenance of analgesia in the intra-operative period. Mannitol, 1 g.kg-1 was given to the patients intraoperatively. Intavenous fluids were given to maintain the central venous pressure of 10 to12 mmHg. At the end of the surgical procedure, residual neuromuscular blockade was antagonized with injection neostigmine 50 μg. kg-1 and injection glycopyrrolate 10 μg.kg-1 i.v.

Baseline (preinduction) arterial blood gas (ABG) was recorded in all patients. This was followed by postinduction ABGs at 1 hourly intervals till the end of the surgery. pH, PCO2, PO2, and HCO3 base deficit or excess and lactate were noted in all patients. Serum lactate of 1.5 mmol.L-1 for males and serum lactate of 2.0 mmol.L-1 for females were taken as the upper limit of normal, as per the institutional laboratory protocol.

ABGs were also noted for all patients in the postoperative period immediately and 12 h later in neurosurgical intensive care unit. Neurological examination was carried at appropriate intervals during the postoperative period for 72 h. Any new-onset postoperative neurodeficit was noted at 12, 24, 48, and 72 h and compared with the preoperative neurodeficit, if present.

Statistical analysis of the correlation between intraoperative hyperlactatemia and fresh postoperative neuro-deficit was done using the Chi-square test.

RESULTS AND OBSERVATIONS

A total of 95 patients were enrolled in the study. Nine patients were excluded from the study, out of which two patients had a history of prior cranial surgical procedure while as seven patients had an altered sensorium (in whom an appropriate neurological examination was not possible in the preoperative period).

Most of the study population was in the age group of 31–50 years with a preponderance of female patients [Table 1].

Table 1

Age distribution of study population

Age (Years)	Male		Female		Total
	No.	%age	No.	%age	No.	%age
0-30	9	24.3	10	20.4	19	22.1
31-50	12	32.4	21	42.9	33	38.4
51-70	12	32.4	18	36.7	30	34.9
≥71	4	10.8	0	0.0	4	4.7
Total	37	100	49	100	86	100

Twenty-five patients (29.1%) had neuro-deficit in the preoperative period, whereas remaining 61 patients (70.9%) had no neuro-deficit [Table 2].

Table 2

Preoperative neuro-deficit in study population

Neuro-deficit	Number	Percentage
Yes	25	29.1
No	61	70.9
Total	86	100

Mean serum lactate was normal initially, 1.35 mmol.L-1 at 0 h. It steadily increased to 8.15 mmol.L-1 at 6 h. Forty-seven (54.65%) patients developed hyperlactatemia during the procedure [Table 3].

Table 3

Mean intraoperative lactate levels at various intervals of time

Time interval	Mean (mmol.L-1)	SD
0 Hour	1.35	0.850
1 Hour	1.64	1.148
2 Hour	1.97	1.309
3 Hour	2.36	1.585
4 Hour	3.71	2.344
5 Hour	4.63	2.764
6 Hour	8.15	0.212

The number of patients with neuro-deficit in the postoperative period at 12, 24, 48, and 72 h, was 30 (34.9%), 32 (37.2%), 39 (45.3%), and 40 (46.5%), respectively [Table 4].

Table 4

Table depicting number and percentage of patients with postoperative neuro-deficit

Postoperative time interval	Patients with postoperative neuro-deficit	% age
12 H	30	34.9
24 H	32	37.2
48 H	39	45.3
72 H	40	46.5

Seven patients, who developed neurodeficit at 72 h, could not be assessed initially as they were sedated and paralyzed. Four patients, who had no neuro-deficit initially, developed it by 72 h. Further, out of the 30 patients who had neuro-deficit at 12 h, three patients recovered by 72 h.

Intraoperatively, serum lactate increased in 45 patients (52.3%) but remained normal in 41 patients (47.7%) [Table 5].

Table 5

Table depicting the number and percentage of patients with increased and normal lactate levels in the intraoperative period

Lactate status	Number	Percentage
Lactate increased	45	52.3
Lactate not increased	41	47.7
Total	86	100

Fresh-onset neuro-deficit developed in 27 patients (31.4%), whereas 59 patients (68.6%) did not develop any fresh-onset neuro-deficit [Table 6].

Table 6

Table depicting the number & percentage of patients with fresh or no neuro-deficit

Fresh neuro-deficit status	Number	Percentage
Fresh neuro-deficit	27	31.4
No fresh-neuro deficit	59	68.6
Total	86	100

Statistical analysis of the correlation between intraoperative hyperlactatemia and fresh postoperative neuro-deficit was done using the Chi-square test. It showed that the correlation was statistically insignificant, P = 0.056 [Table 7].

Table 7

Correlation of intraoperative hyperlactatemia with development of fresh neuro-deficit

Intraoperative lactate levels	Fresh neuro-deficit		No fresh neuro-deficit		Total
	No.	%age	No.	%age
Lactate increased	10	22.22	35	77.77	45
Lactate not increased	17	41.46	24	58.53	41
Total	27	-	59	-	86

Chi-square=3.688; P=0.056 (Not significant)

DISCUSSION

Our study aimed to investigate the prevalence of hyperlactatemia and its association with the development of fresh onset neuro-deficits in patients undergoing craniotomy for various neurosurgical procedures. In our study, the total mean age was 41.7 (±17.0) years, whereas mean age in patients with normal lactate was 44.6 (±16.9) years and those with increased lactate were 38.9 (±16.9) years. There was a preponderance of female patients.

A similar study was done by Brallier et al.[4] Their study was retrospective in comparison to our study wherein we performed prospective data compilation. In their study, 205 (47.01%) patients had normal intraoperative lactate, whereas 231 (52.98%) patients had increased intraoperative lactate. In our study, 41 (47.7%) patients had normal intraoperative lactate whereas 45 (52.3%) patients had increased intraoperative lactate and new neuro-deficit was found in 15 (7.3%) patients in the normal lactate group and in 34 (14.7%) patients in the high lactate group. In our study, postoperatively new neuro-deficit was found in 17 (63.0%) patients who had normal intraoperative serum lactate levels and in 10 (37.0%) patients who had developed intraoperative hyperlactatemia. We had a higher incidence of new neuro-deficit which was possible as a result of the varied and complex pathologies in our surgical population.

They suggested that in some cases serum lactate may be an early marker of regional cerebral hypoperfusion and that localized areas of anaerobic metabolism could be associated with raised serum lactate. Further they observed that patients with elevated lactate had longer hospital stay. They reasoned that intraoperative serum lactate in craniotomy patients may be a result of direct cerebral compression or a change in regional metabolism.

A prospective study on the topic was taken up by the same group of researchers (Romano et al.[5] ) to validate the findings of the previous retrospective study.

The number of patients in our study (86 patients) was comparable with the study of Romano et al.(81 patients). They noted maximum intraoperative serum lactate and categorized them into two groups: patients with maximum lactate <2.0 mmol.L-1 and patients with maximum lactate >2.0 mmol.L-1. In their study, male gender preponderance was seen with a total of 46 (56.8%) male patients, 29 (52.7%) male patients in the normal lactate group, and 17 (65.4%) male patients in the high lactate group. This was in contrast to the results seen in our study where we had a female (49 [57.0%]) gender preponderance.

In their study, 55 (67.9%) patients had normal intraoperative lactate and 26 (32.09%) patients had increased intraoperative lactate. This was in contrast to increased intraoperative levels seen in our study. The higher lactate levels seen in our patient population could be possibly a result of more dehydration in the preoperative period, increased duration of surgery, hypothermia in intraoperative period, and to the complexity of the surgical procedure involved.

In their study, an interim analysis on 81 patients did not reveal any association of intraoperative hyperlactatemia with postoperative new neuro-deficit and study enrollment was terminated due to futility (futility index 0.16). The authors of this cohort study on elective craniotomy patients concluded that serum lactate was not associated with new postoperative neurologic deficits, other end organ events, or 30 day mortality. Serum lactate was, however, related to longer hospital stay.

In our study, fresh postoperative neurodeficit was seen in 17 (41.46%) patients with normal intraoperative lactate levels and in 10 (22.22%) patients with increased intraoperative lactate levels. The correlation between intraoperative hyperlactatemia and fresh neuro-deficit was statistically insignificant (Chi square = 3.688, P = 0.056).

Our findings are consistent with those of de Smalen et al.,[8] who retrospectively studied 496 neurosurgical patients to assess the various factors associated with hyperlactatemia and its impact with postoperative outcome. They divided the patients into groups of normal (≤2 mmol.L-1) or elevated (>2 mmol.L-1) serum lactate at high dependency unit (HDU) admission. Increased neurological deficits were observed in 20 (25.6%) patients in the normal lactate group and in 19 (23.2%) patients in the elevated lactate group (P = 0.716). Hence, this study showed that hyperlactatemia on HDU admission is not correlated with increased postoperative neurodeficit.

Our observations are also supported by KohliSeth R et al. who retrospectively evaluated the incidence and significance of elevated serum lactate and its impact on outcome in 273 postoperative neurosurgical patients included in the study. The authors concluded that postoperative hyperlactatemia occurs frequently in neurosurgery patients but appears benign and not associated with mortality.

Our results are also corroborated by other studies which could not find any role for serum lactate to predict postoperative survival or mortality in craniotomy patients. Cata et al.[9] conducted a retrospective study to evaluate if serum lactate could be used as biomarker to predict the survival in patients with glioblastoma. Their analysis indicated that the intraoperative levels of lactate were not independently associated with changes in survival. They concluded that the serum concentrations of lactate cannot be used as a biomarker to predict survival after glioblastoma surgery.

Therefore, it appears that hyperlactatemia during craniotomy may have other causes or be benign. Paradoxically, emerging studies have pointed toward possible beneficial role of lactate in craniotomy surgeries and traumatic brain injury. It has been postulated that during stress on brain, lactate may be released in the body for feeding into the tricarboxylic acid cycle of neurons (the astrocyte-neuron lactate shuttle hypothesis).[10]

De Smalen et al.[8] have noted recent studies suggesting a neuroprotective role for lactate as it serves as a substrate for oxidation under certain conditions. Authors consider that raised lactate could be an innate protective mechanism, activated during iatrogenic brain injury (i.e., craniotomy).

The serum lactate measured intraoperatively may well be mobilized to help the brain in situations of traumatic or surgical stress rather than being a product of traumatic disruption or surgical manipulation. Rice et al.[11] have reported significant improvement in cognitive ability in rats following brain injury when lactate was infused compared to saline infusion. The authors have claimed clinical relevance for this effect and have stated that lactate may represent a safe, fully available therapeutic option after moderate brain injury.

To conclude, our study revealed that there is no correlation between elevated intraoperative serum lactate and fresh-onset postoperative neurodeficits. To evaluate the clinical significance of hyperlactatemia during craniotomies need more studies to focus on the true role of endogenous lactate in conditions of brain stress. Simultaneously, other means of predicting postoperative fresh-onset neurodeficits need to be explored.

CONCLUSION

The prevalence of intraoperative hyperlactatemia in the study population was found out to be 52.3%, whereas the prevalence of postoperative fresh-onset neuro-deficits was 31.4%.

However, our prospective observational study did not reveal any correlation between intraoperative hyperlactatemia and postoperative fresh onset neuro-deficits in patients undergoing elective craniotomies.

Instead, emerging studies have hinted toward paradoxical neuroprotective role of lactate during craniotomy procedures.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.